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PLoS Comput Biol

Title:		"Structure-Based Sequence Alignment of the Transmembrane Domains of All Human GPCRs: Phylogenetic, Structural and Functional Implications"
Author(s):		Cvicek V; Goddard WA; Abrol R;
Address:		"Materials and Process Simulation Center, California Institute of Technology, Pasadena, California, United States of America. Minnesota Supercomputing Institute, University of Minnesota, Minneapolis, Minnesota, United States of America. Departments of Biomedical Sciences and Medicine, Cedars-Sinai Medical Center, Los Angeles, California, United States of America"
Journal Title:		PLoS Comput Biol
Year:		2016
Volume:		20160330
Issue:		3
Page Number:		e1004805 -
DOI:		10.1371/journal.pcbi.1004805
ISSN/ISBN:		1553-7358 (Electronic) 1553-734X (Print) 1553-734X (Linking)
Abstract:		"The understanding of G-protein coupled receptors (GPCRs) is undergoing a revolution due to increased information about their signaling and the experimental determination of structures for more than 25 receptors. The availability of at least one receptor structure for each of the GPCR classes, well separated in sequence space, enables an integrated superfamily-wide analysis to identify signatures involving the role of conserved residues, conserved contacts, and downstream signaling in the context of receptor structures. In this study, we align the transmembrane (TM) domains of all experimental GPCR structures to maximize the conserved inter-helical contacts. The resulting superfamily-wide GpcR Sequence-Structure (GRoSS) alignment of the TM domains for all human GPCR sequences is sufficient to generate a phylogenetic tree that correctly distinguishes all different GPCR classes, suggesting that the class-level differences in the GPCR superfamily are encoded at least partly in the TM domains. The inter-helical contacts conserved across all GPCR classes describe the evolutionarily conserved GPCR structural fold. The corresponding structural alignment of the inactive and active conformations, available for a few GPCRs, identifies activation hot-spot residues in the TM domains that get rewired upon activation. Many GPCR mutations, known to alter receptor signaling and cause disease, are located at these conserved contact and activation hot-spot residue positions. The GRoSS alignment places the chemosensory receptor subfamilies for bitter taste (TAS2R) and pheromones (Vomeronasal, VN1R) in the rhodopsin family, known to contain the chemosensory olfactory receptor subfamily. The GRoSS alignment also enables the quantification of the structural variability in the TM regions of experimental structures, useful for homology modeling and structure prediction of receptors. Furthermore, this alignment identifies structurally and functionally important residues in all human GPCRs. These residues can be used to make testable hypotheses about the structural basis of receptor function and about the molecular basis of disease-associated single nucleotide polymorphisms"
Keywords:		"Algorithms *Amino Acid Sequence Computational Biology/*methods Databases, Protein Humans Models, Molecular Phylogeny *Protein Structure, Tertiary Receptors, G-Protein-Coupled/*chemistry/metabolism Sequence Alignment/*methods Sequence Analysis, Protein/*me;"
Notes:		"MedlineCvicek, Vaclav Goddard, William A 3rd Abrol, Ravinder eng R01 AI040567/AI/NIAID NIH HHS/ R01 NS073115/NS/NINDS NIH HHS/ R01NS073115/NS/NINDS NIH HHS/ R01AI040567/AI/NIAID NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. 2016/03/31 PLoS Comput Biol. 2016 Mar 30; 12(3):e1004805. doi: 10.1371/journal.pcbi.1004805. eCollection 2016 Mar"