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      • Record: found
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      Is Open Access

      Critical role of the finger loop in arrestin binding to the receptors

      1 , 2 , 1 , *

      PLoS ONE

      Public Library of Science

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          Abstract

          We tested the interactions with four different G protein-coupled receptors (GPCRs) of arrestin-3 mutants with substitutions in the four loops, three of which contact the receptor in the structure of the arrestin-1-rhodopsin complex. Point mutations in the loop at the distal tip of the N-domain (Glu157Ala), in the C-loop (Phe255Ala), back loop (Lys313Ala), and one of the mutations in the finger loop (Gly65Pro) had mild variable effects on receptor binding. In contrast, the deletion of Gly65 at the beginning of the finger loop reduced the binding to all GPCRs tested, with the binding to dopamine D2 receptor being affected most dramatically. Thus, the presence of a glycine at the beginning of the finger loop appears to be critical for the arrestin-receptor interaction.

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          Most cited references 66

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          The G-protein-coupled receptors in the human genome form five main families. Phylogenetic analysis, paralogon groups, and fingerprints.

          The superfamily of G-protein-coupled receptors (GPCRs) is very diverse in structure and function and its members are among the most pursued targets for drug development. We identified more than 800 human GPCR sequences and simultaneously analyzed 342 unique functional nonolfactory human GPCR sequences with phylogenetic analyses. Our results show, with high bootstrap support, five main families, named glutamate, rhodopsin, adhesion, frizzled/taste2, and secretin, forming the GRAFS classification system. The rhodopsin family is the largest and forms four main groups with 13 sub-branches. Positions of the GPCRs in chromosomal paralogons regions indicate the importance of tetraploidizations or local gene duplication events for their creation. We also searched for "fingerprint" motifs using Hidden Markov Models delineating the putative inter-relationship of the GRAFS families. We show several common structural features indicating that the human GPCRs in the GRAFS families share a common ancestor. This study represents the first overall map of the GPCRs in a single mammalian genome. Our novel approach of analyzing such large and diverse sequence sets may be useful for studies on GPCRs in other genomes and divergent protein families.
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            Structural diversity of G protein-coupled receptors and significance for drug discovery.

            G protein-coupled receptors (GPCRs) are the largest family of membrane-bound receptors and also the targets of many drugs. Understanding of the functional significance of the wide structural diversity of GPCRs has been aided considerably in recent years by the sequencing of the human genome and by structural studies, and has important implications for the future therapeutic potential of targeting this receptor family. This article aims to provide a comprehensive overview of the five main human GPCR families--Rhodopsin, Secretin, Adhesion, Glutamate and Frizzled/Taste2--with a focus on gene repertoire, general ligand preference, common and unique structural features, and the potential for future drug discovery.
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              Trends in GPCR drug discovery: new agents, targets and indications

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                Author and article information

                Contributors
                Role: InvestigationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: Investigation
                Role: ConceptualizationRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                15 March 2019
                2019
                : 14
                : 3
                Affiliations
                [1 ] Department of Pharmacology, Vanderbilt University, Nashville, United States of America
                [2 ] University of Applied Sciences Emden/Leer, Emden, Germany
                Indian Institute of Technology Kanpur, INDIA
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Article
                PONE-D-18-29351
                10.1371/journal.pone.0213792
                6420155
                30875392
                © 2019 Zheng et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Counts
                Figures: 4, Tables: 0, Pages: 14
                Product
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: GM122491
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000053, National Eye Institute;
                Award ID: EY011500
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100006537, Vanderbilt University;
                Award ID: Cornelius Vanderbilt Endowed Chair
                Award Recipient :
                Funded by National Institutes of Health, GM122491 (VVG); National Eye Institute, EY011500 (VVG); Vanderbilt University, Cornelius Vanderbilt Endowed Chair (VVG). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Biochemistry
                Proteins
                Transmembrane Receptors
                G Protein Coupled Receptors
                Biology and Life Sciences
                Cell Biology
                Signal Transduction
                Transmembrane Receptors
                G Protein Coupled Receptors
                Research and Analysis Methods
                Chemical Characterization
                Binding Analysis
                Receptor Binding Assays
                Biology and Life Sciences
                Genetics
                Mutation
                Substitution Mutation
                Biology and Life Sciences
                Biochemistry
                Proteins
                Post-Translational Modification
                Phosphorylation
                Physical Sciences
                Chemistry
                Chemical Compounds
                Organic Compounds
                Amino Acids
                Aliphatic Amino Acids
                Glycine
                Physical Sciences
                Chemistry
                Organic Chemistry
                Organic Compounds
                Amino Acids
                Aliphatic Amino Acids
                Glycine
                Biology and Life Sciences
                Biochemistry
                Proteins
                Amino Acids
                Aliphatic Amino Acids
                Glycine
                Research and Analysis Methods
                Precipitation Techniques
                Immunoprecipitation
                Research and Analysis Methods
                Imaging Techniques
                Bioluminescence Imaging
                Bioluminescence Resonance Energy Transfer
                Research and Analysis Methods
                Chemical Characterization
                Optical Analysis
                Bioluminescence Imaging
                Bioluminescence Resonance Energy Transfer
                Physical Sciences
                Physics
                Condensed Matter Physics
                Solid State Physics
                Crystallography
                Crystal Structure
                Custom metadata
                All relevant data are within the paper and its Supporting Information files.

                Uncategorized

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