Comparison of Three GPCR Structural Templates for Modeling of the P2Y12 Nucleotide Receptor

Overview

Journal J Comput Aided Mol Des

Publisher Springer

Specialties Biomedical Engineering
Molecular Biology

Date 2011 Apr 5

PMID 21461952

Citations 17

Authors

Francesca Deflorian

Kenneth A Jacobson

Affiliations

Soon will be listed here.

Abstract

The P2Y(12) receptor (P2Y(12)R) is an ADP-activated G protein-coupled receptor (GPCR) that is an important target for antithrombotic drugs. Three homology models of P2Y(12)R were compared, based on different GPCR structural templates: bovine rhodopsin (bRHO), human A(2A) adenosine receptor (A(2A)AR), and human C-X-C chemokine receptor type 4 (CXCR4). By criteria of sequence analysis (25.6% identity in transmembrane region), deviation from helicity in the second transmembrane helix (TM2), docked poses of ligands highlighting the role of key residues, accessibility of a conserved disulfide bridge that is reactive toward irreversibly-binding antagonists, and the presence of a shared disulfide bridge between the third extracellular loop (EL3) and the N-terminus, the CXCR4-based model appeared to be the most consistent with known characteristics of P2Y(12)R. The docked poses of agonist 2MeSADP and charged anthraquinone antagonist PSB-0739 in the binding pocket of P2Y(12)R-CXC agree with previously published site-directed mutagenesis studies of Arg256 and Lys280. A sulfonate at position 2 of the anthraquinone core created a strong interaction with the Lys174(EL2) side chain. The docking poses of the irreversibly-binding, active metabolite (existing as two diastereoisomers in vivo) of the clinically utilized antagonist Clopidogrel were compared. The free thiol group of the 4S diastereoisomer, but not the 4R isomer, was found in close proximity (~4.7 Å) to the sulfur atom of a disulfide bridge involving Cys175, suggesting greater activity in covalent binding. Therefore, ligand docking to the CXCR4-based model of the P2Y(12)R predicted poses of both reversibly and irreversibly-binding small molecules, consistent with observed pharmacology and mutagenesis studies.

Citing Articles

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Membrane Environment Modulates Ligand-Binding Propensity of P2Y12 Receptor.

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Molecular Modeling Applied to the Discovery of New Lead Compounds for P2 Receptors Based on Natural Sources.

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Prostaglandin E glyceryl ester is an endogenous agonist of the nucleotide receptor P2Y.

Bruser A, Zimmermann A, Crews B, Sliwoski G, Meiler J, Konig G Sci Rep. 2017; 7(1):2380.

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