Journal
PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS
Volume 56, Issue 1, Pages 67-84Publisher
WILEY
DOI: 10.1002/prot.20108
Keywords
G-protein coupled receptor; rhodopsin; adrenergic; molecular modeling; active conformation; inactive conformation; docking; agonist; antagonist
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Using sets of experimental distance restraints, which characterize active or inactive receptor conformations, and the X-ray crystal structure of the inactive form of bovine rhodopsin as a starting point, we have constructed models of both the active and inactive forms of rhodopsin and the beta(2)-adrenergic G-protein coupled receptors (GPCRs). The distance restraints were obtained from published data for site-directed crosslinking, engineered zinc binding, site-directed spin-labeling, IR spectroscopy, and cysteine accessibility studies conducted on class A GPCRs. Molecular dynamics simulations in the presence of either active or inactive restraints were used to generate two distinguishable receptor models. The process for generating the inactive and active models was validated by the hit rates, yields, and enrichment factors determined for the selection of antagonists in the inactive model and for the selection of agonists in the active model from a set of nonadrenergic GPCR drug-like ligands in a virtual screen using ligand docking software. The simulation results provide new insights into the relationships observed between selected biochemical data, the crystal structure of rhodopsin, and the structural rearrangements that occur during activation. (C) 2004 WiIey-Liss, Inc.
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