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FoldGPCR: Structure prediction protocol for the transmembrane domain of G protein-coupled receptors from class A

Authors

  • Mayako Michino,

    1. Department of Molecular Biology, The Scripps Research Institute, 10550 N. Torrey Pines Rd, La Jolla, CA 92037
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    • Mayako Michino's current address is European Molecular Biology Laboratory (EMBL), Structural and Computational Biology Unit, Meyerhofstrasse 1, 69117 Heidelberg, Germany

  • Jianhan Chen,

    1. Department of Biochemistry, Kansas State University, Manhattan, KS 66506
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  • Raymond C. Stevens,

    1. Departments of Molecular Biology and Chemistry, The Scripps Research Institute, La Jolla, CA 92037
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  • Charles L. Brooks III

    Corresponding author
    1. Department of Chemistry and Biophysics Program, University of Michigan, 930 N University Ave, Ann Arbor, MI 48109
    • Department of Chemistry and Biophysics Program, University of Michigan, 930 N University Ave, Ann Arbor, MI 48109
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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 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 β2-adrenergic receptor (β2AR) bound to carazolol, using contacts derived from the template structure of bovine rhodopsin. Comparison with the X-ray crystal structure of the β2AR shows that our protocol is particularly successful in accurately capturing helix backbone irregularities and helix-helix packing interactions that distinguish rhodopsin from β2AR. Proteins 2010. © 2010 Wiley-Liss, Inc.

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