Identification of a Different Agonist-Binding Site and Activation Mechanism of the Human P2Y1 Receptor. Issue 1 (December 2017)

• Record Type: Journal Article
• Authors: Li, Yang; Yin, Can; Liu, Pi; Li, Dongmei; Lin, Jianping
• Is Part Of: Scientific reports. Volume 7:Issue 1(2017)
• Page Start: 1
• Page End: 10
• Publication Date: 2017-12
• Subjects: Natural history -- Research -- Periodicals; Biology -- Research -- Periodicals; Physical sciences -- Research -- Periodicals; Earth sciences -- Research -- Periodicals; Environmental sciences -- Research -- Periodicals; 502.85
• DOI: 10.1038/s41598-017-14268-1
• Languages: English
• ISSNs: 2045-2322

Abstract

Abstract The human P2Y1 receptor (P2Y1 R) is a purinergic G-protein-coupled receptor (GPCR) that functions as a receptor for adenosine 5′-diphosphate (ADP). An antagonist of P2Y1 R might potentially have antithrombotic effects, whereas agonists might serve as antidiabetic agents. On the basis of the antagonist-bound MRS2500-P2Y1 R crystal structure, we constructed computational models of apo-P2Y1 R and the agonist-receptor complex 2MeSADP-P2Y1 R. We then performed conventional molecular dynamics (cMD) and accelerated molecular dynamics (aMD) simulations to study the conformational dynamics after binding with agonist/antagonist as well as the P2Y1 R activation mechanism. We identified a new agonist-binding site of P2Y1 R that is consistent with previous mutagenesis data. This new site is deeper than those of the agonist ADP in the recently simulated ADP-P2Y1 R structure and the antagonist MRS2500 in the MRS2500-P2Y1 R crystal structure. During P2Y1 R activation, the cytoplasmic end of helix VI shifts outward 9.1 Å, the Ser1463.47 -Tyr2375.58 hydrogen bond breaks, a Tyr2375.58 -Val2626.37 hydrogen bond forms, and the conformation of the χ1 rotamer of Phe2696.44 changes from parallel to perpendicular to helix VI. The apo-P2Y1 R system and the MRS2500-P2Y1 R system remain inactive. The newly identified agonist binding site and activation mechanism revealed in this study may aid in the design of P2Y1 R antagonists/agonists as antithrombotic/antidiabetic agents, respectively.