title: On the applicability of GPCR homology models to computer-aided drug discovery: a comparison between in silico and crystal structures of the beta2-adrenergic receptor.
abstract: The publication of the crystal structure of the beta2-adrenergic receptor (beta2-AR) proved that G protein-coupled receptors (GPCRs) share a structurally conserved rhodopsin-like 7TM core. Here, to probe to which extent realistic GPCR structures can be recreated through modeling, carazolol was docked at two rhodopsin-based homology models of the human beta 2-AR. The first featured a rhodopsin-like second extracellular loop, which interfered with ligand docking and with the orientation of several residues in the binding pocket. The second featured a second extracellular loop built completely de novo, which afforded a more accurate model of the binding pocket and a better docking of the ligand. Furthermore, incorporating available biochemical and computational data to the model by correcting the conformation of a single residue lining the binding pocket --Phe290(6.52)--, resulted in significantly improved docking poses. These results support the applicability of GPCR modeling to the design of site-directed mutagenesis experiments and to drug discovery.
authors.affiliation: Laboratory of Biological Modeling, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, MD 20892, USA. stefanoc@mail.nih.gov
authors.forename: Stefano
authors.initials: S
authors.lastname: Costanzi
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D011412:Propanolamines / Q000737:chemistry; D011487:Protein Conformation; D018343:Receptors, Adrenergic, beta-2 / Q000737:chemistry*; D012243:Rhodopsin / Q000737:chemistry; D017386:Sequence Homology, Amino Acid
chemical_list: D011412:Propanolamines; D018343:Receptors, Adrenergic, beta-2; C014382:carazolol; D012243:Rhodopsin