Structure Modeling of All Identified G Protein–Coupled Receptors in the Human Genome

Zhang, Yang; DeVries, Mark E.; Skolnick, Jeffrey

Title:

Structure Modeling of All Identified G Protein–Coupled Receptors in the Human Genome

dc.contributor.author	Zhang, Yang
dc.contributor.author	DeVries, Mark E.
dc.contributor.author	Skolnick, Jeffrey
dc.contributor.corporatename	State University of New York at Buffalo. Center of Excellence in Bioinformatics
dc.date.accessioned	2009-01-30T17:16:04Z
dc.date.available	2009-01-30T17:16:04Z
dc.date.issued	2006-02
dc.description	©2006 Zhang 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.
dc.description	DOI: 10.1371/journal.pcbi.0020013
dc.description.abstract	G protein–coupled receptors (GPCRs), encoded by about 5% of human genes, comprise the largest family of integral membrane proteins and act as cell surface receptors responsible for the transduction of endogenous signal into a cellular response. Although tertiary structural information is crucial for function annotation and drug design, there are few experimentally determined GPCR structures. To address this issue, we employ the recently developed threading assembly refinement (TASSER) method to generate structure predictions for all 907 putative GPCRs in the human genome. Unlike traditional homology modeling approaches, TASSER modeling does not require solved homologous template structures; moreover, it often refines the structures closer to native. These features are essential for the comprehensive modeling of all human GPCRs when close homologous templates are absent. Based on a benchmarked confidence score, approximately 820 predicted models should have the correct folds. The majority of GPCR models share the characteristic seven-transmembrane helix topology, but 45 ORFs are predicted to have different structures. This is due to GPCR fragments that are predominantly from extracellular or intracellular domains as well as database annotation errors. Our preliminary validation includes the automated modeling of bovine rhodopsin, the only solved GPCR in the Protein Data Bank. With homologous templates excluded, the final model built by TASSER has a global Ca root-mean-squared deviation from native of 4.6 A°, with a root-mean-squared deviation in the transmembrane helix region of 2.1A°. Models of several representative GPCRs are compared with mutagenesis and affinity labeling data, and consistent agreement is demonstrated. Structure clustering of the predicted models shows that GPCRs with similar structures tend to belong to a similar functional class even when their sequences are diverse. These results demonstrate the usefulness and robustness of the in silico models for GPCR functional analysis.	en
dc.identifier.citation	PLoS Computational Biology, 2006:2(2): 88-99	en
dc.identifier.issn	1553-7358
dc.identifier.uri	http://hdl.handle.net/1853/26882
dc.language.iso	en_US	en
dc.publisher	Georgia Institute of Technology	en
dc.publisher.original	Public Library of Science
dc.subject	G protein-coupled receptors	en
dc.subject	GPCR models	en
dc.subject	Human genome
dc.subject	Signal transduction
dc.title	Structure Modeling of All Identified G Protein–Coupled Receptors in the Human Genome	en
dc.type	Text
dc.type.genre	Article
dspace.entity.type	Publication
local.contributor.author	Skolnick, Jeffrey
local.contributor.corporatename	College of Sciences
local.contributor.corporatename	School of Biological Sciences
local.contributor.corporatename	Center for the Study of Systems Biology
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