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  Subjects -> CHEMISTRY (Total: 841 journals)
    - ANALYTICAL CHEMISTRY (50 journals)
    - CHEMISTRY (593 journals)
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CHEMISTRY (593 journals)                  1 2 3 | Last

Showing 1 - 200 of 735 Journals sorted alphabetically
2D Materials     Hybrid Journal   (Followers: 8)
Accreditation and Quality Assurance: Journal for Quality, Comparability and Reliability in Chemical Measurement     Hybrid Journal   (Followers: 26)
ACS Catalysis     Full-text available via subscription   (Followers: 34)
ACS Chemical Neuroscience     Full-text available via subscription   (Followers: 18)
ACS Combinatorial Science     Full-text available via subscription   (Followers: 23)
ACS Macro Letters     Full-text available via subscription   (Followers: 23)
ACS Medicinal Chemistry Letters     Full-text available via subscription   (Followers: 39)
ACS Nano     Full-text available via subscription   (Followers: 233)
ACS Photonics     Full-text available via subscription   (Followers: 11)
ACS Synthetic Biology     Full-text available via subscription   (Followers: 21)
Acta Chemica Iasi     Open Access   (Followers: 2)
Acta Chimica Sinica     Full-text available via subscription   (Followers: 1)
Acta Chimica Slovaca     Open Access   (Followers: 1)
Acta Chromatographica     Full-text available via subscription   (Followers: 9)
Acta Facultatis Medicae Naissensis     Open Access  
Acta Metallurgica Sinica (English Letters)     Hybrid Journal   (Followers: 5)
Acta Scientifica Naturalis     Open Access   (Followers: 2)
adhäsion KLEBEN & DICHTEN     Hybrid Journal   (Followers: 5)
Adhesion Adhesives & Sealants     Hybrid Journal   (Followers: 7)
Adsorption Science & Technology     Full-text available via subscription   (Followers: 5)
Advanced Functional Materials     Hybrid Journal   (Followers: 50)
Advanced Science Focus     Free   (Followers: 3)
Advances in Chemical Engineering and Science     Open Access   (Followers: 55)
Advances in Chemical Science     Open Access   (Followers: 13)
Advances in Chemistry     Open Access   (Followers: 14)
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Advances in Nanoparticles     Open Access   (Followers: 15)
Advances in Organometallic Chemistry     Full-text available via subscription   (Followers: 15)
Advances in Polymer Science     Hybrid Journal   (Followers: 41)
Advances in Protein Chemistry     Full-text available via subscription   (Followers: 18)
Advances in Protein Chemistry and Structural Biology     Full-text available via subscription   (Followers: 19)
Advances in Quantum Chemistry     Full-text available via subscription   (Followers: 5)
Advances in Science and Technology     Full-text available via subscription   (Followers: 12)
African Journal of Bacteriology Research     Open Access  
African Journal of Chemical Education     Open Access   (Followers: 2)
African Journal of Pure and Applied Chemistry     Open Access   (Followers: 7)
Agrokémia és Talajtan     Full-text available via subscription   (Followers: 2)
Alkaloids: Chemical and Biological Perspectives     Full-text available via subscription   (Followers: 3)
AMB Express     Open Access   (Followers: 1)
Ambix     Hybrid Journal   (Followers: 3)
American Journal of Biochemistry and Biotechnology     Open Access   (Followers: 68)
American Journal of Biochemistry and Molecular Biology     Open Access   (Followers: 14)
American Journal of Chemistry     Open Access   (Followers: 26)
American Journal of Plant Physiology     Open Access   (Followers: 14)
American Mineralogist     Hybrid Journal   (Followers: 14)
Analyst     Full-text available via subscription   (Followers: 40)
Angewandte Chemie     Hybrid Journal   (Followers: 224)
Angewandte Chemie International Edition     Hybrid Journal   (Followers: 213)
Annales UMCS, Chemia     Open Access   (Followers: 1)
Annals of Clinical Chemistry and Laboratory Medicine     Open Access   (Followers: 3)
Annual Reports in Computational Chemistry     Full-text available via subscription   (Followers: 3)
Annual Reports Section A (Inorganic Chemistry)     Full-text available via subscription   (Followers: 4)
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Annual Review of Chemical and Biomolecular Engineering     Full-text available via subscription   (Followers: 12)
Annual Review of Food Science and Technology     Full-text available via subscription   (Followers: 15)
Anti-Infective Agents     Hybrid Journal   (Followers: 3)
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Applied Organometallic Chemistry     Hybrid Journal   (Followers: 7)
Applied Spectroscopy     Full-text available via subscription   (Followers: 23)
Applied Surface Science     Hybrid Journal   (Followers: 28)
Arabian Journal of Chemistry     Open Access   (Followers: 6)
ARKIVOC     Open Access   (Followers: 2)
Asian Journal of Biochemistry     Open Access   (Followers: 1)
Atomization and Sprays     Full-text available via subscription   (Followers: 4)
Australian Journal of Chemistry     Hybrid Journal   (Followers: 7)
Autophagy     Hybrid Journal   (Followers: 2)
Avances en Quimica     Open Access   (Followers: 1)
Biochemical Pharmacology     Hybrid Journal   (Followers: 10)
Biochemistry     Full-text available via subscription   (Followers: 295)
Biochemistry Insights     Open Access   (Followers: 6)
Biochemistry Research International     Open Access   (Followers: 6)
BioChip Journal     Hybrid Journal  
Bioinorganic Chemistry and Applications     Open Access   (Followers: 9)
Bioinspired Materials     Open Access   (Followers: 5)
Biointerface Research in Applied Chemistry     Open Access   (Followers: 2)
Biointerphases     Open Access   (Followers: 1)
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Biomacromolecules     Full-text available via subscription   (Followers: 19)
Biomass Conversion and Biorefinery     Partially Free   (Followers: 10)
Biomedical Chromatography     Hybrid Journal   (Followers: 6)
Biomolecular NMR Assignments     Hybrid Journal   (Followers: 3)
BioNanoScience     Partially Free   (Followers: 4)
Bioorganic & Medicinal Chemistry     Hybrid Journal   (Followers: 119)
Bioorganic & Medicinal Chemistry Letters     Hybrid Journal   (Followers: 97)
Bioorganic Chemistry     Hybrid Journal   (Followers: 10)
Biopolymers     Hybrid Journal   (Followers: 18)
Biosensors     Open Access   (Followers: 2)
Biotechnic and Histochemistry     Hybrid Journal   (Followers: 1)
Bitácora Digital     Open Access  
Boletin de la Sociedad Chilena de Quimica     Open Access  
Bulletin of the Chemical Society of Ethiopia     Open Access   (Followers: 2)
Bulletin of the Chemical Society of Japan     Full-text available via subscription   (Followers: 24)
Bulletin of the Korean Chemical Society     Hybrid Journal   (Followers: 1)
C - Journal of Carbon Research     Open Access   (Followers: 3)
Cakra Kimia (Indonesian E-Journal of Applied Chemistry)     Open Access  
Canadian Association of Radiologists Journal     Full-text available via subscription   (Followers: 3)
Canadian Journal of Chemistry     Hybrid Journal   (Followers: 10)
Canadian Mineralogist     Full-text available via subscription   (Followers: 3)
Carbohydrate Research     Hybrid Journal   (Followers: 26)
Carbon     Hybrid Journal   (Followers: 66)
Catalysis for Sustainable Energy     Open Access   (Followers: 7)
Catalysis Reviews: Science and Engineering     Hybrid Journal   (Followers: 8)
Catalysis Science and Technology     Free   (Followers: 6)
Catalysis Surveys from Asia     Hybrid Journal   (Followers: 3)
Catalysts     Open Access   (Followers: 8)
Cellulose     Hybrid Journal   (Followers: 7)
Cereal Chemistry     Full-text available via subscription   (Followers: 4)
ChemBioEng Reviews     Full-text available via subscription   (Followers: 1)
ChemCatChem     Hybrid Journal   (Followers: 8)
Chemical and Engineering News     Free   (Followers: 13)
Chemical Bulletin of Kazakh National University     Open Access  
Chemical Communications     Full-text available via subscription   (Followers: 70)
Chemical Engineering Research and Design     Hybrid Journal   (Followers: 23)
Chemical Research in Chinese Universities     Hybrid Journal   (Followers: 3)
Chemical Research in Toxicology     Full-text available via subscription   (Followers: 19)
Chemical Reviews     Full-text available via subscription   (Followers: 175)
Chemical Science     Open Access   (Followers: 22)
Chemical Technology     Open Access   (Followers: 16)
Chemical Vapor Deposition     Hybrid Journal   (Followers: 5)
Chemical Week     Full-text available via subscription   (Followers: 8)
Chemie in Unserer Zeit     Hybrid Journal   (Followers: 57)
Chemie-Ingenieur-Technik (Cit)     Hybrid Journal   (Followers: 26)
ChemInform     Hybrid Journal   (Followers: 8)
Chemistry & Biodiversity     Hybrid Journal   (Followers: 6)
Chemistry & Biology     Full-text available via subscription   (Followers: 30)
Chemistry & Industry     Hybrid Journal   (Followers: 5)
Chemistry - A European Journal     Hybrid Journal   (Followers: 142)
Chemistry - An Asian Journal     Hybrid Journal   (Followers: 15)
Chemistry and Materials Research     Open Access   (Followers: 18)
Chemistry Central Journal     Open Access   (Followers: 4)
Chemistry Education Research and Practice     Free   (Followers: 5)
Chemistry in Education     Open Access   (Followers: 9)
Chemistry International     Hybrid Journal   (Followers: 2)
Chemistry Letters     Full-text available via subscription   (Followers: 44)
Chemistry of Materials     Full-text available via subscription   (Followers: 258)
Chemistry of Natural Compounds     Hybrid Journal   (Followers: 9)
Chemistry World     Full-text available via subscription   (Followers: 22)
Chemistry-Didactics-Ecology-Metrology     Open Access   (Followers: 1)
ChemistryOpen     Open Access   (Followers: 2)
Chemkon - Chemie Konkret, Forum Fuer Unterricht Und Didaktik     Hybrid Journal  
Chemoecology     Hybrid Journal   (Followers: 3)
Chemometrics and Intelligent Laboratory Systems     Hybrid Journal   (Followers: 15)
Chemosensors     Open Access  
ChemPhysChem     Hybrid Journal   (Followers: 9)
ChemPlusChem     Hybrid Journal   (Followers: 2)
ChemTexts     Hybrid Journal  
CHIMIA International Journal for Chemistry     Full-text available via subscription   (Followers: 2)
Chinese Journal of Chemistry     Hybrid Journal   (Followers: 6)
Chinese Journal of Polymer Science     Hybrid Journal   (Followers: 10)
Chromatographia     Hybrid Journal   (Followers: 24)
Clay Minerals     Full-text available via subscription   (Followers: 10)
Cogent Chemistry     Open Access  
Colloid and Interface Science Communications     Open Access  
Colloid and Polymer Science     Hybrid Journal   (Followers: 10)
Colloids and Surfaces B: Biointerfaces     Hybrid Journal   (Followers: 7)
Combinatorial Chemistry & High Throughput Screening     Hybrid Journal   (Followers: 4)
Combustion Science and Technology     Hybrid Journal   (Followers: 18)
Comments on Inorganic Chemistry: A Journal of Critical Discussion of the Current Literature     Hybrid Journal   (Followers: 2)
Composite Interfaces     Hybrid Journal   (Followers: 6)
Comprehensive Chemical Kinetics     Full-text available via subscription   (Followers: 2)
Comptes Rendus Chimie     Full-text available via subscription  
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Computational and Theoretical Chemistry     Hybrid Journal   (Followers: 9)
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Computational Chemistry     Open Access   (Followers: 2)
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Coordination Chemistry Reviews     Full-text available via subscription   (Followers: 2)
Copernican Letters     Open Access   (Followers: 1)
Critical Reviews in Biochemistry and Molecular Biology     Hybrid Journal   (Followers: 5)
Crystal Structure Theory and Applications     Open Access   (Followers: 3)
CrystEngComm     Full-text available via subscription   (Followers: 12)
Current Catalysis     Hybrid Journal   (Followers: 2)
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Current Science     Open Access   (Followers: 58)
Dalton Transactions     Full-text available via subscription   (Followers: 22)
Detection     Open Access   (Followers: 2)
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Diamond and Related Materials     Hybrid Journal   (Followers: 12)
Dislocations in Solids     Full-text available via subscription  
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Drying Technology: An International Journal     Hybrid Journal   (Followers: 4)
Eclética Química     Open Access   (Followers: 1)
Ecological Chemistry and Engineering S     Open Access   (Followers: 4)
Ecotoxicology and Environmental Contamination     Open Access  
Educación Química     Open Access   (Followers: 1)
Education for Chemical Engineers     Hybrid Journal   (Followers: 5)
EJNMMI Radiopharmacy and Chemistry     Open Access  
Elements     Full-text available via subscription   (Followers: 2)
Environmental Chemistry     Hybrid Journal   (Followers: 8)
Environmental Chemistry Letters     Hybrid Journal   (Followers: 4)
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Environmental Science : Nano     Partially Free   (Followers: 1)
Environmental Toxicology & Chemistry     Hybrid Journal   (Followers: 17)

        1 2 3 | Last

Journal Cover Advances in Protein Chemistry and Structural Biology
  [SJR: 1.5]   [H-I: 62]   [19 followers]  Follow
    
   Full-text available via subscription Subscription journal
   ISSN (Online) 1876-1623
   Published by Elsevier Homepage  [3044 journals]
  • Chapter Six Enzymology of Microbial Dimethylsulfoniopropionate Catabolism
    • Authors: Mishtu Dey
      Pages: 195 - 222
      Abstract: Publication date: 2017
      Source:Advances in Protein Chemistry and Structural Biology, Volume 109
      Author(s): Mishtu Dey
      The biochemistry of dimethylsulfoniopropionate (DMSP) catabolism is reviewed. The microbes that catalyze the reactions central to DMSP catabolic pathways are described, and the focus is on the enzymology of the process. Approximately 109 tons of DMSP is released annually by marine eukaryotes as an osmolyte. A vast majority of DMSP is assimilated by bacteria through either a demethylation or lyase pathways, producing either the methane thiol or the volatile dimethylsulfide (DMS), respectively. Enzymatic breakdown of DMSP generates ~107 tons of DMS annually, which may have impact on global climate. DMS also acts as a chemoattractant for zooplanktons and seabirds. Both DMSP and DMS play a key role in the global sulfur cycle and are key nutrients for marine microbial growth. Important enzymes in the biochemical pathways of DMSP catabolism are covered in this review, with a focus on the latest developments in their mechanism.

      PubDate: 2017-07-29T09:19:22Z
      DOI: 10.1016/bs.apcsb.2017.05.001
      Issue No: Vol. 109 (2017)
       
  • Analysis of Protein Interactions by Surface Plasmon Resonance
    • Abstract: Publication date: Available online 12 September 2017
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Dennis G. Drescher, Dakshnamurthy Selvakumar, Marian J. Drescher
      Surface plasmon resonance is an optical technique that is utilized for detecting molecular interactions, such as interactions that occur between proteins or other classes of molecules. Binding of a mobile molecule (analyte) to a molecule immobilized on a thin metal film (ligand) changes the refractive index of the film. The angle of extinction of light that is completely reflected after polarized light impinges upon the film, is altered and monitored as a change in detector position for a dip in reflected intensity (the surface plasmon resonance phenomenon). Because the method strictly detects mass, there is no need to label the interacting components, thus eliminating possible changes of their molecular properties. In this chapter, we review essential SPR methodology and present applications to basic science and human disease.

      PubDate: 2017-09-18T04:43:08Z
       
  • Using TR-FRET to Investigate Protein–Protein Interactions: A Case Study
           of PXR-Coregulator Interaction
    • Authors: Wenwei Lin; Taosheng Chen
      Abstract: Publication date: Available online 31 August 2017
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Wenwei Lin, Taosheng Chen
      Time-resolved fluorescence resonance energy transfer (TR-FRET) protein–protein interaction assays, especially in the format of receptor coregulator (coactivator and corepressor) recruitment/repression assays, have been widely used in nuclear receptor research to characterize the modes of action, efficacies, and binding affinities of ligands (including their properties as agonists, antagonists, and inverse agonists). However, there has been only limited progress in using this assay format for pregnane X receptor (PXR). In this chapter, we discuss TR-FRET protein–protein interaction assays and focus on a novel PXR TR-FRET coactivator interaction assay that we have developed based on a PXR coactivator cocrystal study. This new PXR TR-FRET coactivator interaction assay can characterize the binding affinities of PXR ligands and also differentiate antagonists from agonists. This assay is very robust, with the signal remaining stable over a long incubation time (up to 300min has been tested). It can tolerate high concentrations of DMSO (up to 5%) and has a high signal-to-noise ratio (six under typical assay conditions). This newly developed PXR TR-FRET coactivator interaction assay has potential application in high-throughput screening to identify and characterize novel PXR agonists and antagonists.

      PubDate: 2017-09-05T23:52:57Z
      DOI: 10.1016/bs.apcsb.2017.06.001
       
  • Structural Prediction of Protein–Protein Interactions by Docking:
           Application to Biomedical Problems
    • Authors: Didier Barradas-Bautista; Mireia Rosell; Chiara Pallara; Juan Fernández-Recio
      Abstract: Publication date: Available online 31 August 2017
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Didier Barradas-Bautista, Mireia Rosell, Chiara Pallara, Juan Fernández-Recio
      A huge amount of genetic information is available thanks to the recent advances in sequencing technologies and the larger computational capabilities, but the interpretation of such genetic data at phenotypic level remains elusive. One of the reasons is that proteins are not acting alone, but are specifically interacting with other proteins and biomolecules, forming intricate interaction networks that are essential for the majority of cell processes and pathological conditions. Thus, characterizing such interaction networks is an important step in understanding how information flows from gene to phenotype. Indeed, structural characterization of protein–protein interactions at atomic resolution has many applications in biomedicine, from diagnosis and vaccine design, to drug discovery. However, despite the advances of experimental structural determination, the number of interactions for which there is available structural data is still very small. In this context, a complementary approach is computational modeling of protein interactions by docking, which is usually composed of two major phases: (i) sampling of the possible binding modes between the interacting molecules and (ii) scoring for the identification of the correct orientations. In addition, prediction of interface and hot-spot residues is very useful in order to guide and interpret mutagenesis experiments, as well as to understand functional and mechanistic aspects of the interaction. Computational docking is already being applied to specific biomedical problems within the context of personalized medicine, for instance, helping to interpret pathological mutations involved in protein–protein interactions, or providing modeled structural data for drug discovery targeting protein–protein interactions.

      PubDate: 2017-09-05T23:52:57Z
      DOI: 10.1016/bs.apcsb.2017.06.003
       
  • Development of Protein–Protein Interaction Inhibitors for the
           Treatment of Infectious Diseases
    • Authors: Andrew F. Voter; James L. Keck
      Abstract: Publication date: Available online 24 August 2017
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Andrew F. Voter, James L. Keck
      Protein–protein interaction (PPI) inhibitors are a rapidly expanding class of therapeutics. Recent advances in our understanding of PPIs and success of early examples of PPI inhibitors demonstrate the feasibility of targeting PPIs. This review summarizes the techniques used for the discovery and optimization of a diverse set PPI inhibitors, focusing on the development of PPI inhibitors as new antibacterial and antiviral agents. We close with a summary of the advances responsible for making PPI inhibitors realistic targets for therapeutic intervention and brief outlook of the field.

      PubDate: 2017-08-29T21:00:12Z
      DOI: 10.1016/bs.apcsb.2017.07.005
       
  • Subcellular Targeting of Nitric Oxide Synthases Mediated by Their
           N-Terminal Motifs
    • Authors: Carlos Costas-Insua; Javier Merino-Gracia; Clara Aicart-Ramos; Ignacio Rodríguez-Crespo
      Abstract: Publication date: Available online 24 August 2017
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Carlos Costas-Insua, Javier Merino-Gracia, Clara Aicart-Ramos, Ignacio Rodríguez-Crespo
      From a catalytic point of view, the three mammalian nitric oxide synthases (NOSs) function in an almost identical way. The N-terminal oxygenase domain catalyzes the conversion of l-arginine to l-citrulline plus ·NO in two sequential oxidation steps. Once l-arginine binds to the active site positioned above the heme moiety, two consecutive monooxygenation reactions take place. In the first step, l-arginine is hydroxylated to make Nω-hydroxy-l-arginine in a process that requires 1 molecule of NADPH and 1 molecule of O2 per mol of l-arginine reacted. In the second step, Nω-hydroxy-l-arginine, never leaving the active site, is oxidized to ·NO plus l-citrulline and 1 molecule of O2 and 0.5 molecules of NADPH are consumed. Since nitric oxide is an important signaling molecule that participates in a number of biological processes, including neurotransmission, vasodilation, and immune response, synthesis and release of ·NO in vivo must be exquisitely regulated both in time and in space. Hence, NOSs have evolved introducing in their amino acid sequences subcellular targeting motifs, most of them located at their N-termini. Deletion studies performed on recombinant, purified NOSs have revealed that part of the N-terminus of all three NOS can be eliminated with the resulting mutant enzymes still being catalytically active. Likewise, NOS isoforms lacking part of their N-terminus when transfected in cells render mislocalized, active proteins. In this review we will comment on the current knowledge of these subcellular targeting signals present in nNOS, iNOS, and eNOS.

      PubDate: 2017-08-29T21:00:12Z
      DOI: 10.1016/bs.apcsb.2017.07.002
       
  • Targeting the Architecture of Deregulated Protein Complexes in Cancer
    • Authors: Eduard Stefan; Jakob Troppmair; Klaus Bister
      Abstract: Publication date: Available online 18 August 2017
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Eduard Stefan, Jakob Troppmair, Klaus Bister
      The architectures of central signaling hubs are precisely organized by static and dynamic protein–protein interactions (PPIs). Upon deregulation, these PPI platforms are capable to propagate or initiate pathophysiological signaling events. This causes the acquisition of molecular features contributing to the etiology or progression of many diseases, including cancer, where deregulated molecular interactions of signaling proteins have been best studied. The reasons for PPI-dependent reprogramming of cancer-initiating cells are manifold; in many cases, mutations perturb PPIs, enzyme activities, protein abundance, or protein localization. Consequently, the pharmaceutical targeting of PPIs promises to be of remarkable therapeutic value. For this review we have selected three key players of oncogenic signaling which are differently affected by PPI deregulation: two (the small G proteins of the RAS family and the transcription factor MYC) are considered “undruggable” using classical drug discovery approaches and in the case of the third protein discussed here, PKA, standard kinase inhibitors, may be unsuitable in the clinic. These circumstances require alternative strategies, which may lie in pharmaceutical drug interference of critical PPIs accountable for oncogenic signaling.

      PubDate: 2017-08-18T16:55:48Z
      DOI: 10.1016/bs.apcsb.2017.07.001
       
  • Protein–Protein Interaction Modulators for Epigenetic Therapies
    • Authors: Bárbara I. Díaz-Eufracio; J. Jesús Naveja; José L. Medina-Franco
      Abstract: Publication date: Available online 25 July 2017
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Bárbara I. Díaz-Eufracio, J. Jesús Naveja, José L. Medina-Franco
      Targeting protein–protein interactions (PPIs) is becoming an attractive approach for drug discovery. This is particularly true for difficult or emerging targets, such as epitargets that may be elusive to drugs that fall into the traditional chemical space. The chemical nature of the PPIs makes attractive the use of peptides or peptidomimetics to selectively modulate such interactions. Despite the fact peptide-based drug discovery has been challenging, the use of peptides as leads compounds for drug discovery is still a valid strategy. This chapter discusses the current status of PPIs in epigenetic drug discovery. A special emphasis is made on peptides and peptide-like compounds as potential drug candidates.

      PubDate: 2017-07-29T09:19:22Z
      DOI: 10.1016/bs.apcsb.2017.06.002
       
  • Intrinsic Disorder, Protein–Protein Interactions, and Disease
    • Authors: Vladimir N. Uversky
      Abstract: Publication date: Available online 24 July 2017
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Vladimir N. Uversky
      It is recognized now that biologically active proteins without stable tertiary structure (known as intrinsically disordered proteins, IDPs) and hybrid proteins containing ordered domains and intrinsically disordered protein regions (IDPRs) are important players found in any given proteome. These IDPs/IDPRs possess functions that complement functional repertoire of their ordered counterparts, being commonly related to recognition, as well as control and regulation of various signaling pathways. They are interaction masters, being able to utilize a wide spectrum of interaction mechanisms, ranging from induced folding to formation of fuzzy complexes where significant levels of disorder are preserved, to polyvalent stochastic interactions playing crucial roles in the liquid–liquid phase transitions leading to the formation of proteinaceous membrane-less organelles. IDPs/IDPRs are tightly controlled themselves via various means, including alternative splicing, precisely controlled expression and degradation, binding to specific partners, and posttranslational modifications. Distortions in the regulation and control of IDPs/IDPRs, as well as their aberrant interactivity are commonly associated with various human diseases. This review presents some aspects of the intrinsic disorder-based functionality and dysfunctionality, paying special attention to the normal and pathological protein–protein interactions.

      PubDate: 2017-07-29T09:19:22Z
      DOI: 10.1016/bs.apcsb.2017.06.005
       
  • Targeting Intramembrane Protein–Protein Interactions: Novel Therapeutic
           Strategy of Millions Years Old
    • Authors: Alexander B. Sigalov
      Abstract: Publication date: Available online 24 July 2017
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Alexander B. Sigalov
      Intramembrane protein–protein interactions (PPIs) are involved in transmembrane signal transduction mediated by cell surface receptors and play an important role in health and disease. Recently, receptor-specific modulatory peptides rationally designed using a general platform of transmembrane signaling, the signaling chain homooligomerization (SCHOOL) model, have been proposed to therapeutically target these interactions in a variety of serious diseases with unmet needs including cancer, sepsis, arthritis, retinopathy, and thrombosis. These peptide drug candidates use ligand-independent mechanisms of action (SCHOOL mechanisms) and demonstrate potent efficacy in vitro and in vivo. Recent studies surprisingly revealed that in order to modify and/or escape the host immune response, human viruses use similar mechanisms and modulate cell surface receptors by targeting intramembrane PPIs in a ligand-independent manner. Here, I review these intriguing mechanistic similarities and discuss how the viral strategies optimized over a billion years of the coevolution of viruses and their hosts can help to revolutionize drug discovery science and develop new, disruptive therapies. Examples are given.

      PubDate: 2017-07-29T09:19:22Z
      DOI: 10.1016/bs.apcsb.2017.06.004
       
  • A Paradigm for CH Bond Cleavage: Structural and Functional Aspects of
           Transition State Stabilization by Mandelate Racemase
    • Authors: Stephen L. Bearne; Martin St. Maurice
      Abstract: Publication date: Available online 9 June 2017
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Stephen L. Bearne, Martin St. Maurice
      Mandelate racemase (MR) from Pseudomonas putida catalyzes the Mg2+-dependent, 1,1-proton transfer reaction that racemizes (R)- and (S)-mandelate. MR shares a partial reaction (i.e., the metal ion-assisted, Brønsted base-catalyzed proton abstraction of the α-proton of carboxylic acid substrates) and structural features ((β/α)7β-barrel and N-terminal α + β capping domains) with a vast group of homologous, yet functionally diverse, enzymes in the enolase superfamily. Mechanistic and structural studies have developed this enzyme into a paradigm for understanding how enzymes such as those of the enolase superfamily overcome kinetic and thermodynamic barriers to catalyze the abstraction of an α-proton from a carbon acid substrate with a relatively high pK a value. Structural studies on MR bound to intermediate/transition state analogues have delineated those structural features that MR uses to stabilize transition states and enhance reaction rates of proton abstraction. Kinetic, site-directed mutagenesis, and structural studies have also revealed that the phenyl ring of the substrate migrates through the hydrophobic cavity within the active site during catalysis and that the Brønsted acid–base catalysts (Lys 166 and His 297) may be utilized as binding determinants for inhibitor recognition. In addition, structural studies on the adduct formed from the irreversible inhibition of MR by 3-hydroxypyruvate revealed that MR can form and deprotonate a Schiff-base with 3-hydroxypyruvate to yield an enol(ate)-aldehyde adduct, suggesting a possible evolutionary link between MR and the Schiff-base forming aldolases. As the archetype of the enolase superfamily, mechanistic and structural studies on MR will continue to enhance our understanding of enzyme catalysis and furnish insights into the evolution of enzyme function.

      PubDate: 2017-06-13T07:14:51Z
      DOI: 10.1016/bs.apcsb.2017.04.007
       
  • Sortase Transpeptidases: Structural Biology and Catalytic Mechanism
    • Authors: Alex W. Jacobitz; Michele D. Kattke; Jeff Wereszczynski; Robert T. Clubb
      Abstract: Publication date: Available online 5 June 2017
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Alex W. Jacobitz, Michele D. Kattke, Jeff Wereszczynski, Robert T. Clubb
      Gram-positive bacteria use sortase cysteine transpeptidase enzymes to covalently attach proteins to their cell wall and to assemble pili. In pathogenic bacteria sortases are potential drug targets, as many of the proteins that they display on the microbial surface play key roles in the infection process. Moreover, the Staphylococcus aureus Sortase A (SaSrtA) enzyme has been developed into a valuable biochemical reagent because of its ability to ligate biomolecules together in vitro via a covalent peptide bond. Here we review what is known about the structures and catalytic mechanism of sortase enzymes. Based on their primary sequences, most sortase homologs can be classified into six distinct subfamilies, called class A–F enzymes. Atomic structures reveal unique, class-specific variations that support alternate substrate specificities, while structures of sortase enzymes bound to sorting signal mimics shed light onto the molecular basis of substrate recognition. The results of computational studies are reviewed that provide insight into how key reaction intermediates are stabilized during catalysis, as well as the mechanism and dynamics of substrate recognition. Lastly, the reported in vitro activities of sortases are compared, revealing that the transpeptidation activity of SaSrtA is at least 20-fold faster than other sortases that have thus far been characterized. Together, the results of the structural, computational, and biochemical studies discussed in this review begin to reveal how sortases decorate the microbial surface with proteins and pili, and may facilitate ongoing efforts to discover therapeutically useful small molecule inhibitors.

      PubDate: 2017-06-08T06:29:55Z
      DOI: 10.1016/bs.apcsb.2017.04.008
       
  • Computational Biochemistry—Enzyme Mechanisms Explored
    • Authors: Martin Culka; Florian Gisdon Matthias Ullmann
      Abstract: Publication date: Available online 27 May 2017
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Martin Culka, Florian J. Gisdon, G. Matthias Ullmann
      Understanding enzyme mechanisms is a major task to achieve in order to comprehend how living cells work. Recent advances in biomolecular research provide huge amount of data on enzyme kinetics and structure. The analysis of diverse experimental results and their combination into an overall picture is, however, often challenging. Microscopic details of the enzymatic processes are often anticipated based on several hints from macroscopic experimental data. Computational biochemistry aims at creation of a computational model of an enzyme in order to explain microscopic details of the catalytic process and reproduce or predict macroscopic experimental findings. Results of such computations are in part complementary to experimental data and provide an explanation of a biochemical process at the microscopic level. In order to evaluate the mechanism of an enzyme, a structural model is constructed which can be analyzed by several theoretical approaches. Several simulation methods can and should be combined to get a reliable picture of the process of interest. Furthermore, abstract models of biological systems can be constructed combining computational and experimental data. In this review, we discuss structural computational models of enzymatic systems. We first discuss various models to simulate enzyme catalysis. Furthermore, we review various approaches how to characterize the enzyme mechanism both qualitatively and quantitatively using different modeling approaches.

      PubDate: 2017-05-29T05:07:08Z
       
  • Striking Diversity in Holoenzyme Architecture and Extensive Conformational
           Variability in Biotin-Dependent Carboxylases
    • Authors: Liang Tong
      Abstract: Publication date: Available online 23 May 2017
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Liang Tong
      Biotin-dependent carboxylases are widely distributed in nature and have central roles in the metabolism of fatty acids, amino acids, carbohydrates, and other compounds. The last decade has seen the accumulation of structural information on most of these large holoenzymes, including the 500-kDa dimeric yeast acetyl-CoA carboxylase, the 750-kDa α6β6 dodecameric bacterial propionyl-CoA carboxylase, 3-methylcrotonyl-CoA carboxylase, and geranyl-CoA carboxylase, the 720-kDa hexameric bacterial long-chain acyl-CoA carboxylase, the 500-kDa tetrameric bacterial single-chain pyruvate carboxylase, the 370-kDa α2β4 bacterial two-subunit pyruvate carboxylase, and the 130-kDa monomeric eukaryotic urea carboxylase. A common theme that has emerged from these studies is the dramatic structural flexibility of these holoenzymes despite their strong overall sequence conservation, evidenced both by the extensive diversity in the architectures of the holoenzymes and by the extensive conformational variability of their domains and subunits. This structural flexibility is crucial for the function and regulation of these enzymes and identifying compounds that can interfere with it represents an attractive approach for developing novel modulators and drugs. The extensive diversity observed in the structures so far and its biochemical and functional implications will be the focus of this review.

      PubDate: 2017-05-24T04:47:30Z
      DOI: 10.1016/bs.apcsb.2017.04.006
       
  • Mechanistic Insights Into Catalytic RNA–Protein Complexes Involved in
           Translation of the Genetic Code
    • Authors: Satya B. Routh; Rajan Sankaranarayanan
      Abstract: Publication date: Available online 19 May 2017
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Satya B. Routh, Rajan Sankaranarayanan
      The contemporary world is an “RNA–protein world” rather than a “protein world” and tracing its evolutionary origins is of great interest and importance. The different RNAs that function in close collaboration with proteins are involved in several key physiological processes, including catalysis. Ribosome—the complex megadalton cellular machinery that translates genetic information encoded in nucleotide sequence to amino acid sequence—epitomizes such an association between RNA and protein. RNAs that can catalyze biochemical reactions are known as ribozymes. They usually employ general acid–base catalytic mechanism, often involving the 2′-OH of RNA that activates and/or stabilizes a nucleophile during the reaction pathway. The protein component of such RNA–protein complexes (RNPCs) mostly serves as a scaffold which provides an environment conducive for the RNA to function, or as a mediator for other interacting partners. In this review, we describe those RNPCs that are involved at different stages of protein biosynthesis and in which RNA performs the catalytic function; the focus of the account is on highlighting mechanistic aspects of these complexes. We also provide a perspective on such associations in the context of proofreading during translation of the genetic code. The latter aspect is not much appreciated and recent works suggest that this is an avenue worth exploring, since an understanding of the subject can provide useful insights into how RNAs collaborate with proteins to ensure fidelity during these essential cellular processes. It may also aid in comprehending evolutionary aspects of such associations.

      PubDate: 2017-05-24T04:47:30Z
      DOI: 10.1016/bs.apcsb.2017.04.002
       
  • Computational Glycobiology: Mechanistic Studies of Carbohydrate-Active
           Enzymes and Implication for Inhibitor Design
    • Authors: Andrew P. Montgomery; Kela Xiao; Xingyong Wang; Danielle Skropeta; Haibo Yu
      Abstract: Publication date: Available online 19 May 2017
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Andrew P. Montgomery, Kela Xiao, Xingyong Wang, Danielle Skropeta, Haibo Yu
      Carbohydrate-active enzymes (CAZymes) are families of essential and structurally related enzymes, which catalyze the creation, modification, and degradation of glycosidic bonds in carbohydrates to maintain essentially all kingdoms of life. CAZymes play a key role in many biological processes underpinning human health and diseases (e.g., cancer, diabetes, Alzheimer's diseases, AIDS) and have thus emerged as important drug targets in the fight against pathogenesis. The realization of the full potential of CAZymes remains a significant challenge, relying on a deeper understanding of the molecular mechanisms of catalysis. Considering numerous unsettled questions in the literature, while with a large amount of structural, kinetic, and mutagenesis data available for CAZymes, there is a pressing need and an abundant opportunity for collaborative computational and experimental investigations with the aim to unlock the secrets of CAZyme catalysis at an atomic level. In this review, we briefly survey key methodology development in computational studies of CAZyme catalysis. This is complemented by selected case studies highlighting mechanistic insights provided by computational glycobiology. Implication for inhibitor design by mimicking the transition state is also illustrated for both glycoside hydrolases and glycosyltransferases. The challenges for such studies will be noted and finally an outlook for future directions will be provided.

      PubDate: 2017-05-24T04:47:30Z
      DOI: 10.1016/bs.apcsb.2017.04.003
       
  • Biology, Mechanism, and Structure of Enzymes in the
           α-d-Phosphohexomutase Superfamily
    • Authors: Kyle M. Stiers; Andrew G. Muenks; Lesa J. Beamer
      Abstract: Publication date: Available online 17 May 2017
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Kyle M. Stiers, Andrew G. Muenks, Lesa J. Beamer
      Enzymes in the α-d-phosphohexomutases superfamily catalyze the reversible conversion of phosphosugars, such as glucose 1-phosphate and glucose 6-phosphate. These reactions are fundamental to primary metabolism across the kingdoms of life and are required for a myriad of cellular processes, ranging from exopolysaccharide production to protein glycosylation. The subject of extensive mechanistic characterization during the latter half of the 20th century, these enzymes have recently benefitted from biophysical characterization, including X-ray crystallography, NMR, and hydrogen–deuterium exchange studies. This work has provided new insights into the unique catalytic mechanism of the superfamily, shed light on the molecular determinants of ligand recognition, and revealed the evolutionary conservation of conformational flexibility. Novel associations with inherited metabolic disease and the pathogenesis of bacterial infections have emerged, spurring renewed interest in the long-appreciated functional roles of these enzymes.

      PubDate: 2017-05-19T03:29:24Z
      DOI: 10.1016/bs.apcsb.2017.04.005
       
  • Collagenolytic Matrix Metalloproteinase Structure–Function
           Relationships: Insights From Molecular Dynamics Studies
    • Authors: Tatyana G. Karabencheva-Christova; Christo Z. Christov; Gregg B. Fields
      Abstract: Publication date: Available online 8 May 2017
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Tatyana G. Karabencheva-Christova, Christo Z. Christov, Gregg B. Fields
      Several members of the zinc-dependent matrix metalloproteinase (MMP) family catalyze collagen degradation. Experimental data reveal a collaboration between different MMP domains in order to achieve efficient collagenolysis. Molecular dynamics (MD) simulations have been utilized to provide atomistic details of the collagenolytic process. The triple-helical structure of collagen exhibits local regions of flexibility, with modulation of interchain salt bridges and water bridges contributing to accessibility of individual chains by the enzyme. In turn, the hemopexin-like (HPX) domain of the MMP initially binds the triple helix and facilitates the presentation of individual strands to active site in the catalytic (CAT) domain. Extensive positive and negative correlated motions are observed between the CAT and HPX domains when collagen is bound. Ultimately, the MD simulation studies have complemented structural (NMR spectroscopy, X-ray crystallography) and kinetic analyses to provide a more detailed mechanistic view of MMP-catalyzed collagenolysis.

      PubDate: 2017-05-14T01:16:32Z
      DOI: 10.1016/bs.apcsb.2017.04.001
       
  • Stress-Induced NLRP3 Inflammasome in Human Diseases
    • Authors: Elísabet Alcocer-Gómez; Beatriz Castejón-Vega; Mario D. Cordero
      Abstract: Publication date: Available online 27 March 2017
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Elísabet Alcocer-Gómez, Beatriz Castejón-Vega, Mario D. Cordero
      Stress is a complex event that induces disturbances to physiological and psychological homeostasis, and it may have a detrimental impact on certain brain and physiological functions. In the last years, a dual role of the stress effect has been studied in order to elucidate the molecular mechanism by which can induce physiological symptoms after psychological stress exposition and vice versa. In this sense, inflammation has been proposed as an important starring. And in the same line, the inflammasome complex has emerged to give responses because of its role of stress sensor. The implication of the same complex, NLRP3 inflammasome, in different diseases such as cardiovascular, neurodegenerative, psychiatric, and metabolic diseases opens a door to develop new therapeutic perspectives.

      PubDate: 2017-03-28T20:30:18Z
      DOI: 10.1016/bs.apcsb.2017.02.002
       
  • A Computational Approach to Identify the Biophysical and Structural
           Aspects of Methylenetetrahydrofolate Reductase (MTHFR) Mutations (A222V,
           E429A, and R594Q) Leading to Schizophrenia
    • Authors: Himani Tanwar; P. Sneha; D. Thirumal Kumar; R. Siva; Charles Emmanuel Jebaraj Walter; C. George Priya Doss
      Abstract: Publication date: Available online 23 March 2017
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Himani Tanwar, P. Sneha, D. Thirumal Kumar, R. Siva, Charles Emmanuel Jebaraj Walter, C. George Priya Doss
      The association between depression and methylenetetrahydrofolate reductase (MTHFR) has been continually demonstrated in clinical studies, yet there are sparse resources available to build a relationship between the mutations associated with MTHFR and depression. The common mutations found to be associated with schizophrenia and MTHFR are A222V, E429A, and R594Q. Although abundant research on structural and functional effects caused by A222V mutation is available, very less amount of studies have been done on the other two mutants (E429A and R594Q). Hence in this study, a comparative analysis was carried out between the most common A222V mutation, a prevalent E429A mutation, and a less prevalent and less deleterious R594Q mutation. To predict structural rearrangements upon mutation, we proposed a computational pipeline using in silico prediction tools, molecular docking, and molecular dynamics simulation analysis. Since the association of flavin adenine dinucleotide (FAD) is important for the functioning of the protein, binding analysis between protein and the coenzyme was performed. This would enable us to understand the interference level of each mutation over FAD-binding activity. Consequently, we found that two mutations (A222V and E429A) showed lesser binding activity and structural deviations when compared to the native molecule and mutant R594Q. Comparatively, higher structural changes were observed with A222V mutant complex in comparison to other mutant complexes. Computational studies like this could render better insights into the structural changes in the protein and their relationship with the disease condition.

      PubDate: 2017-03-28T20:30:18Z
      DOI: 10.1016/bs.apcsb.2017.01.007
       
  • Neuroinflammation in Alzheimer's Disease: The Preventive and Therapeutic
           Potential of Polyphenolic Nutraceuticals
    • Authors: Yousef Sawikr; Nagendra Sastry Yarla; Ilaria Peluso; Mohammad Amjad Kamal; Gjumrakch Aliev; Anupam Bishayee
      Abstract: Publication date: Available online 22 March 2017
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Yousef Sawikr, Nagendra Sastry Yarla, Ilaria Peluso, Mohammad Amjad Kamal, Gjumrakch Aliev, Anupam Bishayee
      Brain inflammation, characterized by increased microglia and astrocyte activation, increases during aging and is a key feature of neurodegenerative diseases, such as Alzheimer's disease (AD). In AD, neuronal death and synaptic impairment, induced by amyloid-β (Aβ) peptide, are at least in part mediated by microglia and astrocyte activation. Glial activation results in the sustained production of proinflammatory cytokines and reactive oxygen species, giving rise to a chronic inflammatory process. Astrocytes are the most abundant glial cells in the central nervous system and are involved in the neuroinflammation. Astrocytes can be activated by numerous factors, including free saturated fatty acids, pathogens, lipopolysaccharide, and oxidative stress. Activation of astrocytes produces inflammatory cytokines and the enzyme cyclooxygenase-2, enhancing the production of Aβ. Furthermore, the role of the receptor for advanced glycation end products/nuclear factor-κB (NF-κB) axis in neuroinflammation is in line with the nonenzymatic glycosylation theory of aging, suggesting a central role of the advanced glycation end products in the age-related cognitive and a possible role of nutraceuticals in the prevention of neuroinflammation and AD. However, modulation of P-glycoprotein, rather than antioxidant and anti-inflammatory effects, could be the major mechanism of polyphenolic compounds, including flavonoids. Curcumin, resvertrol, piperine, and other polyphenols have been explored as novel therapeutic and preventive agents for AD. The aim of this review is to critically analyze and discuss the mechanisms involved in neuroinflammation and the possible role of nutraceuticals in the prevention and therapy of AD by targeting neuroinflammation.

      PubDate: 2017-03-28T20:30:18Z
      DOI: 10.1016/bs.apcsb.2017.02.001
       
  • Analyzing the Effect of V66M Mutation in BDNF in Causing Mood Disorders: A
           Computational Approach
    • Authors: Sneha Thirumal; Kumar Sugandhi Saini Kreeti Kajal Magesh Siva George
      Abstract: Publication date: Available online 9 March 2017
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): P. Sneha, D. Thirumal Kumar, Sugandhi Saini, Kreeti Kajal, R. Magesh, R. Siva, C. George Priya Doss
      Mental disorders or mood disorders are prevalent globally irrespective of region, race, and ethnic groups. Of the types of mood disorders, major depressive disorder (MDD) and bipolar disorder (BPD) are the most prevalent forms of psychiatric condition. A number of preclinical studies emphasize the essential role of brain-derived neurotrophic factor (BDNF) in the pathophysiology of mood disorders. Additionally, BDNF is the most common growth factor in the central nervous system along with their essential role during the neural development and the synaptic elasticity. A malfunctioning of this protein is associated with many types of mood disorders. The variant methionine replaces valine at 66th position is strongly related to BPD, and an individual with a homozygous condition of this allele is at a greater risk of developing MDD. There are very sparse reports suggesting the structural changes of the protein occurring upon the mutation. Consequently, in this study, we applied a computational pipeline to understand the effects caused by the mutation on the protein's structure and function. With the use of in silico tools and computational macroscopic methods, we identified a decrease in the alpha-helix nature, and an overall increase in the random coils that could have probably resulted in deformation of the protein.

      PubDate: 2017-03-09T16:01:25Z
       
  • Oxidative Stress: Love and Hate History in Central Nervous System
    • Authors: Genaro Gabriel Ortiz; Fermín P. Pacheco Moisés; Mario Mireles-Ramírez; Luis J. Flores-Alvarado; Héctor González-Usigli; Víctor J. Sánchez-González; Angélica L. Sánchez-López; Lorenzo Sánchez-Romero; Eduardo I. Díaz-Barba; J. Francisco Santoscoy-Gutiérrez; Paloma Rivero-Moragrega
      Abstract: Publication date: Available online 7 March 2017
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Genaro Gabriel Ortiz, Fermín P. Pacheco Moisés, Mario Mireles-Ramírez, Luis J. Flores-Alvarado, Héctor González-Usigli, Víctor J. Sánchez-González, Angélica L. Sánchez-López, Lorenzo Sánchez-Romero, Eduardo I. Díaz-Barba, J. Francisco Santoscoy-Gutiérrez, Paloma Rivero-Moragrega
      Molecular oxygen is essential for aerobic organisms in order to synthesize large amounts of energy during the process of oxidative phosphorylation and it is harnessed in the form of adenosine triphosphate, the chemical energy of the cell. Oxygen is toxic for anaerobic organisms but it is also less obvious that oxygen is poisonous to aerobic organisms at higher concentrations of oxygen. For instance, oxygen toxicity is a condition resulting from the harmful effects of breathing molecular oxygen at increased partial pressures. Reactive oxygen species (ROS) are chemically reactive molecules containing oxygen that are formed as a natural byproduct of the normal metabolism of oxygen and have important roles in cell signaling and homeostasis. However, in pathological conditions ROS levels can increase dramatically. This may result in significant damage to cell structures. Living organisms have been adapted to the ROS in two ways: they can mitigate the unwanted effects through removal by the antioxidant systems and can advantageously use them as messengers in cell signaling and regulation of body functions. Some other physiological functions of ROS include the regulation of vascular tone, detection, and adaptation to hypoxia. In this review, we describe the mechanisms of oxidative damage and its relationship with the most highly studied neurodegenerative diseases.

      PubDate: 2017-03-09T16:01:25Z
      DOI: 10.1016/bs.apcsb.2017.01.003
       
  • Inflammation in Epileptic Encephalopathies
    • Authors: Oleksii Shandra; Solomon L. Moshé; Aristea S. Galanopoulou
      Abstract: Publication date: Available online 28 February 2017
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Oleksii Shandra, Solomon L. Moshé, Aristea S. Galanopoulou
      West syndrome (WS) is an infantile epileptic encephalopathy that manifests with infantile spasms (IS), hypsarrhythmia (in ~60% of infants), and poor neurodevelopmental outcomes. The etiologies of WS can be structural–metabolic pathologies (~60%), genetic (12%–15%), or of unknown origin. The current treatment options include hormonal treatment (adrenocorticotropic hormone and high-dose steroids) and the GABA aminotransferase inhibitor vigabatrin, while ketogenic diet can be given as add-on treatment in refractory IS. There is a need to identify new therapeutic targets and more effective treatments for WS. Theories about the role of inflammatory pathways in the pathogenesis and treatment of WS have emerged, being supported by both clinical and preclinical data from animal models of WS. Ongoing advances in genetics have revealed numerous genes involved in the pathogenesis of WS, including genes directly or indirectly involved in inflammation. Inflammatory pathways also interact with other signaling pathways implicated in WS, such as the neuroendocrine pathway. Furthermore, seizures may also activate proinflammatory pathways raising the possibility that inflammation can be a consequence of seizures and epileptogenic processes. With this targeted review, we plan to discuss the evidence pro and against the following key questions. Does activation of inflammatory pathways in the brain cause epilepsy in WS and does it contribute to the associated comorbidities and progression? Can activation of certain inflammatory pathways be a compensatory or protective event? Are there interactions between inflammation and the neuroendocrine system that contribute to the pathogenesis of WS? Does activation of brain inflammatory signaling pathways contribute to the transition of WS to Lennox–Gastaut syndrome? Are there any lead candidates or unexplored targets for future therapy development for WS targeting inflammation?

      PubDate: 2017-03-03T12:44:54Z
      DOI: 10.1016/bs.apcsb.2017.01.005
       
  • Molecular Targets of Ascochlorin and Its Derivatives for Cancer Therapy
    • Authors: Jason Chua Min-Wen; Benjamin Chua Yan-Jiang; Srishti Mishra; Xiaoyun Dai; Junji Magae; Ng Shyh-Chang; Alan Prem Kumar; Gautam Sethi
      Abstract: Publication date: Available online 15 February 2017
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Jason Chua Min-Wen, Benjamin Chua Yan-Jiang, Srishti Mishra, Xiaoyun Dai, Junji Magae, Ng Shyh-Chang, Alan Prem Kumar, Gautam Sethi
      Cancer is an extremely complex disease comprising of a multitude of characteristic hallmarks that continue to evolve with time. At the genomic level, random mutations leading to deregulation of diverse oncogenic signal transduction cascades and polymorphisms coupled with environmental as well as life style-related factors are major causative agent contributing to chemoresistance and the failure of conventional therapies as well as molecular targeted agents. Hence, there is an urgent need to identify novel alternative therapies based on alternative medicines to combat this dreaded disease. Ascochlorin (ASC), an isoprenoid antibiotic isolated initially from the fermented broth of Ascochyta viciae, and its synthetic derivatives have recently demonstrated substantial antineoplastic effects in a variety of tumor cell lines and mouse models. The major focus of this review article is to briefly analyze the chemopreventive as well as therapeutic properties of ASC and its derivatives and to identify the multiple molecular targets modulated by this novel class of anticancer agent.

      PubDate: 2017-02-17T07:31:15Z
      DOI: 10.1016/bs.apcsb.2017.01.001
       
  • Stress-Adaptive Response in Ovarian Cancer Drug Resistance: Role of TRAP1
           in Oxidative Metabolism-Driven Inflammation
    • Authors: Maria Rosaria Amoroso; Danilo Swann Matassa; Ilenia Agliarulo; Rosario Avolio; Francesca Maddalena; Valentina Condelli; Matteo Landriscina; Franca Esposito
      Abstract: Publication date: Available online 12 February 2017
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Maria Rosaria Amoroso, Danilo Swann Matassa, Ilenia Agliarulo, Rosario Avolio, Francesca Maddalena, Valentina Condelli, Matteo Landriscina, Franca Esposito
      Metabolic reprogramming is one of the most frequent stress-adaptive response of cancer cells to survive environmental changes and meet increasing nutrient requirements during their growth. These modifications involve cellular bioenergetics and cross talk with surrounding microenvironment, in a dynamic network that connect different molecular processes, such as energy production, inflammatory response, and drug resistance. Even though the Warburg effect has long been considered the main metabolic feature of cancer cells, recent reports identify mitochondrial oxidative metabolism as a driving force for tumor growth in an increasing number of cellular contexts. In recent years, oxidative phosphorylation has been linked to a remodeling of inflammatory response due to autocrine or paracrine secretion of interleukines that, in turn, induces a regulation of gene expression involving, among others, molecules responsible for the onset of drug resistance. This process is especially relevant in ovarian cancer, characterized by low survival, high frequency of disease relapse and chemoresistance. Recently, the molecular chaperone TRAP1 (tumor necrosis factor-associated protein 1) has been identified as a key junction molecule in these processes in ovarian cancer: in fact, TRAP1 mediates a metabolic switch toward oxidative phosphorylation that, in turn, triggers cytokines secretion, with consequent gene expression remodeling, finally leading to cisplatin resistance and epithelial-to-mesenchymal transition in ovarian cancer models. This review summarizes how metabolism, chemoresistance, inflammation, and epithelial-to-mesenchymal transition are strictly interconnected, and how TRAP1 stays at the crossroads of these processes, thus shedding new lights on molecular networks at the basis of ovarian cancer.

      PubDate: 2017-02-17T07:31:15Z
      DOI: 10.1016/bs.apcsb.2017.01.004
       
  • Cardiokines as Modulators of Stress-Induced Cardiac Disorders
    • Authors: Anna Planavila; Joaquim Fernández-Solà; Francesc Villarroya
      Abstract: Publication date: Available online 10 February 2017
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Anna Planavila, Joaquim Fernández-Solà, Francesc Villarroya
      Almost 30 years ago, the protein, atrial natriuretic peptide, was identified as a heart-secreted hormone that provides a peripheral signal from the myocardium that communicates to the rest of the organism to modify blood pressure and volume under conditions of heart failure. Since then, additional peripheral factors secreted by the heart, termed cardiokines, have been identified and shown to coordinate this interorgan cross talk. In addition to this interorgan communication, cardiokines also act in an autocrine/paracrine manner to play a role in intercellular communication within the myocardium. This review focuses on the roles of newly emerging cardiokines that are mainly increased in stress-induced cardiac diseases. The potential of these cardiokines as clinical biomarkers for diagnosis and prognosis of cardiac disorders is also discussed.

      PubDate: 2017-02-11T02:26:12Z
      DOI: 10.1016/bs.apcsb.2017.01.002
       
  • Targeting IKK and NF-κB for Therapy
    • Authors: J.K. Durand; A.S. Baldwin
      Abstract: Publication date: Available online 11 January 2017
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): J.K. Durand, A.S. Baldwin
      In addition to regulating immune responses, the NF-κB family of transcription factors also promotes cellular proliferation and survival. NF-κB and its activating kinase, IKK, have become appealing therapeutic targets because of their critical roles in the progression of many diseases including chronic inflammation and cancer. Here, we discuss the conditions that lead to pathway activation, the effects of constitutive activation, and some of the strategies used to inhibit NF-κB signaling.

      PubDate: 2017-01-13T18:51:36Z
      DOI: 10.1016/bs.apcsb.2016.11.006
       
  • Elucidating the Mutational Landscape in Hepatocyte Nuclear Factor 1β
           (HNF1B) by Computational Approach
    • Authors: Sneha C.G.P.; Doss
      Abstract: Publication date: Available online 3 January 2017
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): P. Sneha, C.G.P. Doss
      Transcription factors are the major gene-regulatory proteins that recognize specific nucleotide sequences and bind to them. Missense mutations in transcription factors play a significant role in misregulation of gene expression contributing to various diseases and disorders. Understanding their structural and functional impact of the disease-causing mutations becomes prime importance in treating a disease. Commonly associated defect with the mutations of hepatocyte nuclear factor 1 beta (HNF1B) protein, a transcription factor results in maturity-onset diabetes of the young-5 (MODY-5) leading to loss of function. In the study presented, we applied a series of computational strategies to analyze the effect of mutations on protein structure or function in protein–DNA complex. The mutations from publicly available databases were retrieved and subjected to an array of in silico prediction methods. Key implementation of the present study consists of a pipeline drawn using well established in silico prediction methods of different algorithms to explain the biochemical changes impaired upon mutations in the binding sites of protein–DNA complex using HNF1B. Prediction scores obtained from the in silico tools suggested H153N and A241T as the major nsSNPs involved in destabilizing the protein. Further, high-end microscopic computational study, such as molecular dynamics simulations was utilized to relate the structural and functional effects upon mutations. Although, both the mutations exhibited similar structural differences, we observed A241T with higher destabilizing effect on the protein. The presented work is a step toward understanding the genotype–phenotype relationships in transcription factor genes using fast and accurate computational approach.

      PubDate: 2017-01-05T17:36:15Z
       
  • The Functional Stability of FOXP3 and RORγt in Treg and Th17 and
           Their Therapeutic Applications
    • Authors: Ren
      Abstract: Publication date: Available online 15 December 2016
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): J. Ren, B. Li
      The balance of CD4+CD25+FOXP3+ regulatory T cells (Tregs) and effector T cells plays a key role in maintaining immune homeostasis, while the imbalance of them is related to many inflammatory diseases in both human and mice. Here we discuss about the plasticity of Tregs and Th17 cells, and the related human diseases resulted from the imbalance of them. Further, we will focus on the mechanisms regulating the plasticity between Tregs and Th17 cells and the potential therapeutic strategies by targeting regulators of the expression and activity of FOXP3 and RORγt or regulators of Treg/Th17 balance in autoimmune diseases, allergy, infection, and cancer.

      PubDate: 2016-12-20T14:47:01Z
       
  • Transcription Factors in Breast Cancer—Lessons From Recent Genomic
           Analyses and Therapeutic Implications
    • Authors: E. Zacksenhaus; J.C. Liu; Z. Jiang; Y. Yao; L. Xia; M. Shrestha; Y. Ben-David
      Abstract: Publication date: Available online 12 December 2016
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): E. Zacksenhaus, J.C. Liu, Z. Jiang, Y. Yao, L. Xia, M. Shrestha, Y. Ben-David
      Multiplatform genomic analyses have identified 93 frequently altered genes in breast cancer. Of these, as many as 49 genes are directly or indirectly involved in transcription. These include constitutive and inducible DNA-binding transcription factors (DB-TFs, 13 genes), corepressors/coactivators (14 genes), epigenetic (10), and mediator/splicing/rRNA (3) factors. At least nine additional genes are immediate upstream regulators of transcriptional cofactors. G:profiler analysis reveals that these alterations affect cell cycle, development/differentiation, steroid hormone, and chromatin modification pathways. A notable observation is that DB-TFs that mediate major oncogenic signaling (e.g., WNT, receptor tyrosine kinase (RTK), NOTCH, and HIPPO), which switch from default repression (signal OFF) to transcriptional activation (signal ON), are not altered in breast cancer. Instead, corepressors (e.g., pRb for E2F1 downstream of various proliferation signals) or upstream factors (e.g., APC and AXIN for TCF, downstream of canonical WNT signaling) are lost, or coactivators (e.g., NOTCH1/2 for CSL/RBPJk) are induced. In contrast, constitutive (MYC, TBX3) and signal-induced (TP53, FOXA1) DB-TFs that do not mediate default repression are directly altered in breast cancer. Some of these TFs have been implicated in the establishment of super-enhancers and positive transcriptional elongation. In addition, oncogenic transcription is induced by mutations affecting regulatory elements or chromatin conformation that create new TF-binding sites in promoters and enhancers of oncogenic genes to promote tumorigenesis. Here we review these diverse oncogenic alterations in TFs in BC and discuss implications for therapy.

      PubDate: 2016-12-12T13:51:49Z
      DOI: 10.1016/bs.apcsb.2016.10.003
       
  • NF-κB as a Therapeutic Target in Inflammatory-Associated Bone
           Diseases
    • Authors: T.-h. Lin; J. Pajarinen; L. Lu; A. Nabeshima; L.A. Cordova; Z. Yao; S.B. Goodman
      Abstract: Publication date: Available online 9 December 2016
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): T.-h. Lin, J. Pajarinen, L. Lu, A. Nabeshima, L.A. Cordova, Z. Yao, S.B. Goodman
      Inflammation is a defensive mechanism for pathogen clearance and maintaining tissue homeostasis. In the skeletal system, inflammation is closely associated with many bone disorders including fractures, nonunions, periprosthetic osteolysis (bone loss around orthopedic implants), and osteoporosis. Acute inflammation is a critical step for proper bone-healing and bone-remodeling processes. On the other hand, chronic inflammation with excessive proinflammatory cytokines disrupts the balance of skeletal homeostasis involving osteoblastic (bone formation) and osteoclastic (bone resorption) activities. NF-κB is a transcriptional factor that regulates the inflammatory response and bone-remodeling processes in both bone-forming and bone-resorption cells. In vitro and in vivo evidences suggest that NF-κB is an important potential therapeutic target for inflammation-associated bone disorders by modulating inflammation and bone-remodeling process simultaneously. The challenges of NF-κB-targeting therapy in bone disorders include: (1) the complexity of canonical and noncanonical NF-κB pathways; (2) the fundamental roles of NF-κB-mediated signaling for bone regeneration at earlier phases of tissue damage and acute inflammation; and (3) the potential toxic effects on nontargeted cells such as lymphocytes. Recent developments of novel inhibitors with differential approaches to modulate NF-κB activity, and the controlled release (local) or bone-targeting drug delivery (systemic) strategies, have largely increased the translational application of NF-κB therapy in bone disorders. Taken together, temporal modulation of NF-κB pathways with the combination of recent advanced bone-targeting drug delivery techniques is a highly translational strategy to reestablish homeostasis in the skeletal system.

      PubDate: 2016-12-12T13:51:49Z
      DOI: 10.1016/bs.apcsb.2016.11.002
       
  • The Complex Role of the ZNF224 Transcription Factor in Cancer
    • Authors: E. Cesaro; G. Sodaro; G. Montano; M. Grosso; A. Lupo; P. Costanzo
      Abstract: Publication date: Available online 5 December 2016
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): E. Cesaro, G. Sodaro, G. Montano, M. Grosso, A. Lupo, P. Costanzo
      ZNF224 is a member of the Kruppel-associated box zinc finger proteins (KRAB-ZFPs) family. It was originally identified as a transcriptional repressor involved in gene-specific silencing through the recruitment of the corepressor KAP1, chromatin-modifying activities, and the arginine methyltransferase PRMT5 on the promoter of its target genes. Recent findings indicate that ZNF224 can behave both as a tumor suppressor or an oncogene in different human cancers. The transcriptional regulatory properties of ZNF224 in these systems appear to be complex and influenced by specific sets of interactors. ZNF224 can also act as a transcription cofactor for other DNA-binding proteins. A role for ZNF224 in transcriptional activation has also emerged. Here, we review the state of the literature supporting both roles of ZNF224 in cancer. We also examine the functional activity of ZNF224 as a transcription factor and the influence of protein partners on its dual behavior. Increasing information on the mechanism through which ZNF224 can operate could lead to the identification of agents capable of modulating ZNF224 function, thus potentially paving the way to new therapeutic strategies for treatment of cancer.

      PubDate: 2016-12-12T13:51:49Z
      DOI: 10.1016/bs.apcsb.2016.11.003
       
  • Transcription Factors as a Target for Vaccination Against Ticks and Mites
    • Authors: O.A.E. Sparagano
      Abstract: Publication date: Available online 5 December 2016
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): O.A.E. Sparagano
      Ticks and mites are well-known ectoparasites as potential vectors for numerous bacteria, viruses, and parasites. Many being blood feeders add to physiological deterioration, morbidity, and mortality of their vertebrate hosts. To control them, transcription factors have been identified and studied in their role to sustain such arthropod pests. This paper summarizes some of the work done on those factors involved during blood feeding, reproduction, or when interacting with their pathogens and symbiont populations. Any transcription factor supporting the equilibrium developed by the ticks/mites could become a potential target for new control methods to prevent some of their key physiological functions.

      PubDate: 2016-12-12T13:51:49Z
      DOI: 10.1016/bs.apcsb.2016.11.004
       
  • HMGB1 Protein: A Therapeutic Target Inside and Outside the Cell
    • Authors: I. Ugrinova; E. Pasheva
      Abstract: Publication date: Available online 2 December 2016
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): I. Ugrinova, E. Pasheva
      High-mobility group box 1 protein (HMGB1) is a nonhistone chromosomal protein discovered more than 30 years ago. It is an abundant nuclear protein that has a dual function—in the nucleus, it binds DNA and participates in practically all DNA-dependent processes serving as an architectural factor. Outside the cell, HMGB1 plays a different role—it acts as an alarmine that activates a large number of HMGB1-“competent” cells and mediates a broad range of physiological and pathological responses. This universality makes it an attractive target for innovative therapeutic strategies in the treatment of various diseases. Here we present an overview of the major nuclear and extracellular properties of HMGB1 and describe its interaction with different molecular partners as specific receptors or inhibitors, which are important for its role as a target in multiple diseases. We highlight its pivotal role as a target for cancer treatment at two aspects: first in terms of its substantial impact on the repair capacity of cancer cells, thus affecting the effectiveness of chemotherapy with the antitumor drug cis-platinum and, second, the possibility to be targeted by microRNAs influencing different pathways of human diseases, thus making it a promising candidate for a new strategy for therapeutic interventions against various pathological conditions but mainly cancer.

      PubDate: 2016-12-05T13:01:11Z
      DOI: 10.1016/bs.apcsb.2016.10.001
       
  • Targeting Chromatin Remodeling in Inflammation and Fibrosis
    • Authors: J. Yang; B. Tian; A.R. Brasier
      Abstract: Publication date: Available online 1 December 2016
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): J. Yang, B. Tian, A.R. Brasier
      Mucosal surfaces of the human body are lined by a contiguous epithelial cell surface that forms a barrier to aerosolized pathogens. Specialized pattern recognition receptors detect the presence of viral pathogens and initiate protective host responses by triggering activation of the nuclear factor κB (NFκB)/RelA transcription factor and formation of a complex with the positive transcription elongation factor (P-TEFb)/cyclin-dependent kinase (CDK)9 and Bromodomain-containing protein 4 (BRD4) epigenetic reader. The RelA·BRD4·P-TEFb complex produces acute inflammation by regulating transcriptional elongation, which produces a rapid genomic response by inactive genes maintained in an open chromatin configuration engaged with hypophosphorylated RNA polymerase II. We describe recent studies that have linked prolonged activation of the RelA–BRD4 pathway with the epithelial–mesenchymal transition (EMT) by inducing a core of EMT corepressors, stimulating secretion of growth factors promoting airway fibrosis. The mesenchymal state produces rewiring of the kinome and reprogramming of innate responses toward inflammation. In addition, the core regulator Zinc finger E-box homeodomain 1 (ZEB1) silences the expression of the interferon response factor 1 (IRF1), required for type III IFN expression. This epigenetic silencing is mediated by the Enhancer of Zeste 2 (EZH2) histone methyltransferase. Because of their potential applications in cancer and inflammation, small-molecule inhibitors of NFκB/RelA, CDK9, BRD4, and EZH2 have been the targets of medicinal chemistry efforts. We suggest that disruption of the RelA·BRD4·P-TEFb pathway and EZH2 methyltransferase has important implications for reversing fibrosis and restoring normal mucosal immunity in chronic inflammatory diseases.

      PubDate: 2016-12-05T13:01:11Z
      DOI: 10.1016/bs.apcsb.2016.11.001
       
 
 
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