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Abstract
The human P2Y1 receptor (P2Y1R) is a purinergic G-protein-coupled receptor (GPCR) that functions as a receptor for adenosine 5′-diphosphate (ADP). An antagonist of P2Y1R might potentially have antithrombotic effects, whereas agonists might serve as antidiabetic agents. On the basis of the antagonist-bound MRS2500-P2Y1R crystal structure, we constructed computational models of apo-P2Y1R and the agonist-receptor complex 2MeSADP-P2Y1R. 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 P2Y1R activation mechanism. We identified a new agonist-binding site of P2Y1R that is consistent with previous mutagenesis data. This new site is deeper than those of the agonist ADP in the recently simulated ADP-P2Y1R structure and the antagonist MRS2500 in the MRS2500-P2Y1R crystal structure. During P2Y1R 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-P2Y1R system and the MRS2500-P2Y1R system remain inactive. The newly identified agonist binding site and activation mechanism revealed in this study may aid in the design of P2Y1R antagonists/agonists as antithrombotic/antidiabetic agents, respectively.
Highlights
The P2Y1 (P2Y1R) and P2Y12 (P2Y12R) receptors are human purinergic G-protein-coupled receptor (GPCR) and are two of the eight members of the human P2YR family[6]
MRS2500 binds to the extracellular vestibule of P2Y1 receptor (P2Y1R), a pocket composed of residues mainly from the N-terminal, ECL2 and extracellular side of helices VI and VII
We performed conventional molecular dynamics (cMD) and accelerated molecular dynamics (aMD) simulations for 2MeSADP-P2Y1R, apo-P2Y1R and MRS2500-P2Y1R embedded in a lipid bilayer/water environment to investigate the conformational dynamics after binding with agonists/antagonists and the P2Y1R activation mechanism
Summary
The P2Y1 (P2Y1R) and P2Y12 (P2Y12R) receptors are human purinergic GPCRs and are two of the eight members of the human P2YR family[6]. It is essential to study the conformational dynamics of P2Y1R after binding with agonists/ antagonists and the activation mechanism of this receptor by using alternative tools. AMD has been successfully used to study many GPCR systems[29,30,31,32,33,34], and aMD simulations at hundreds of nanoseconds have been shown to capture events that occur on millisecond scale[29,35] While this manuscript was in preparation, Yuan et al published long-timescale cMD simulations on P2Y1R using Schrödinger Desmond software[36]. We performed cMD and aMD simulations for 2MeSADP-P2Y1R, apo-P2Y1R and MRS2500-P2Y1R embedded in a lipid bilayer/water environment to investigate the conformational dynamics after binding with agonists/antagonists and the P2Y1R activation mechanism. The apo-P2Y1R system and the MRS2500-P2Y1R system remain in the inactive state
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