title: FoldGPCR: structure prediction protocol for the transmembrane domain of G protein-coupled receptors from class A.
abstract: 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 A C alpha 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 beta(2)-adrenergic receptor (beta(2)AR) bound to carazolol, using contacts derived from the template structure of bovine rhodopsin. Comparison with the X-ray crystal structure of the beta(2)AR shows that our protocol is particularly successful in accurately capturing helix backbone irregularities and helix-helix packing interactions that distinguish rhodopsin from beta(2)AR.
authors.affiliation: Department of Molecular Biology, The Scripps Research Institute, 10550 N. Torrey Pines Rd, La Jolla, CA 92037, USA.
authors.forename: Mayako
authors.initials: M
authors.lastname: Michino
authors.forename: Jianhan
authors.initials: J
authors.lastname: Chen
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Stevens
authors.forename: Charles L
authors.initials: CL
authors.lastname: Brooks
mesh_terms: D058672:Adrenergic beta-2 Receptor Antagonists; D000319:Adrenergic beta-Antagonists / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D002417:Cattle; D019295:Computational Biology; D003198:Computer Simulation; D005103:Expert Systems; D006801:Humans; D008024:Ligands; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D011412:Propanolamines / Q000737:chemistry / Q000378:metabolism; D054730:Protein Interaction Domains and Motifs; D017433:Protein Structure, Secondary; D018343:Receptors, Adrenergic, beta-2 / Q000737:chemistry / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry* / Q000378:metabolism; D012243:Rhodopsin / Q000737:chemistry; D012984:Software; D013696:Temperature
chemical_list: D058672:Adrenergic beta-2 Receptor Antagonists; D000319:Adrenergic beta-Antagonists; D008024:Ligands; D008565:Membrane Proteins; D011412:Propanolamines; D018343:Receptors, Adrenergic, beta-2; D043562:Receptors, G-Protein-Coupled; C014382:carazolol; D012243:Rhodopsin