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FoldGPCR: Structure prediction protocol for the transmembrane domain of G protein‐coupled receptors from class A
Author(s) -
Michino Mayako,
Chen Jianhan,
Stevens Raymond C.,
Brooks Charles L.
Publication year - 2010
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.22731
Subject(s) - rhodopsin , g protein coupled receptor , transmembrane domain , helix bundle , homology modeling , computational biology , helix (gastropod) , protein structure , chemistry , protein structure prediction , membrane protein , crystallography , bioinformatics , biology , receptor , biochemistry , membrane , retinal , ecology , snail , enzyme
Building reliable structural models of G protein‐coupled receptors (GPCRs) is a difficult task because of the paucity of suitable templates, low sequence identity, and the wide variety of ligand specificities within the superfamily. Template‐based modeling is known to be the most successful method for protein structure prediction. However, refinement of homology models within 1–3 Å Cα RMSD of the native structure remains a major challenge. Here, we address this problem by developing a novel protocol (foldGPCR) for modeling the transmembrane (TM) region of GPCRs in complex with a ligand, aimed to accurately model the structural divergence between the template and target in the TM helices. The protocol is based on predicted conserved inter‐residue contacts between the template and target, and exploits an all‐atom implicit membrane force field. The placement of the ligand in the binding pocket is guided by biochemical data. The foldGPCR protocol is implemented by a stepwise hierarchical approach, in which the TM helical bundle and the ligand are assembled by simulated annealing trials in the first step, and the receptor‐ligand complex is refined with replica exchange sampling in the second step. The protocol is applied to model the human β 2 ‐adrenergic receptor (β 2 AR) bound to carazolol, using contacts derived from the template structure of bovine rhodopsin. Comparison with the X‐ray crystal structure of the β 2 AR shows that our protocol is particularly successful in accurately capturing helix backbone irregularities and helix‐helix packing interactions that distinguish rhodopsin from β 2 AR. Proteins 2010. © 2010 Wiley‐Liss, Inc.