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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.

SUBMITTER: Costanzi S

PROVIDER: S-EPMC2443693 | biostudies-literature | 2008 May

REPOSITORIES: biostudies-literature

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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.

Costanzi Stefano S

Journal of medicinal chemistry 20080429 10

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 ...[more]

PMID: 18442228

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Project description:PurposeG protein-coupled receptors (GPCRs) are a superfamily of membrane proteins of vast pharmaceutical interest. Here, we describe a graph theory-based analysis of the structure of the β2 adrenergic receptor (β2 AR), a prototypical GPCR. In particular, we illustrate the network of direct and indirect interactions that link each amino acid residue to any other residue of the receptor.MethodsNetworks of interconnected amino acid residues in proteins are analogous to social networks of interconnected people. Hence, they can be studied through the same analysis tools typically employed to analyze social networks - or networks in general - to reveal patterns of connectivity, influential members, and dynamicity. We focused on the analysis of closeness-centrality, which is a measure of the overall connectivity distance of the member of a network to all other members.ResultsThe residues endowed with the highest closeness-centrality are located in the middle of the seven transmembrane domains (TMs). In particular, they are mostly located in the middle of TM2, TM3, TM6 or TM7, while fewer of them are located in the middle of TM1, TM4 or TM5. At the cytosolic end of TM6, the centrality detected for the active structure is markedly lower than that detected for the corresponding residues in the inactive structures. Moreover, several residues acquire centrality when the structures are analyzed in the presence of ligands. Strikingly, there is little overlap between the residues that acquire centrality in the presence of the ligand in the blocker-bound structures and the agonist-bound structures.ConclusionsOur results reflect the fact that the receptor resembles a bow tie, with a rather tight knot of closely interconnected residues and two ends that fan out in two opposite directions: one toward the extracellular space, which hosts the ligand binding cavity, and one toward the cytosol, which hosts the G protein binding cavity. Moreover, they underscore how interaction network is by the conformational rearrangements concomitant with the activation of the receptor and by the presence of agonists or blockers.

Dataset Information

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.

Publications

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.

Similar Datasets

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