Molecular mechanism of action for reversible P2Y12 antagonists

Hu, Ge; Peng, Yong; Xiao, Pei‐Gen; Xu, Jing

doi:10.1016/j.bpc.2011.03.001

Cited by 10 publications

(3 citation statements)

References 47 publications

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“…These findings correspond to our functional analysis, because at both positions no side‐chain variations are tolerated (see Supplemental Table S2). It is of interest to note that Lys 280 has been implicated in direct agonist interaction (46,47). One may speculate that ADP‐induced disruption of the Tyr 259 /Lys 280 hydrogen bond (inactive state) participates in triggering conformational changes during receptor activation.…”

Section: Discussionmentioning

confidence: 99%

Using ortholog sequence data to predict the functional relevance of mutations in G‐protein‐coupled receptors

et al. 2012

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Evaluating the functional relevance of naturally occurring gene variants usually requires experimental testing or is even impossible because of the lack of appropriate functional assays. Here we have analyzed whether comparative sequence data from orthologs are suitable to predict the functional relevance of mutations in a model protein, a G-protein-coupled receptor for ADP (P2Y(12)). The functional effect of every possible substitution at each amino acid position within a portion of P2Y(12) (1254 mutants) was individually determined. Sequence analysis of >70 P2Y(12) vertebrate orthologs revealed that this amino acid variability ensuring proper receptor function in vivo highly correlates (>90%) with the in vitro experimental data. Therefore, ortholog sequence data are helpful to predict the functional relevance of individual positions and mutations for P2Y(12). It is likely that similar conclusions may be extended for other GPCRs and conserved proteins as well.

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Section: Discussionmentioning

confidence: 99%

Using ortholog sequence data to predict the functional relevance of mutations in G‐protein‐coupled receptors

et al. 2012

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“…Experimental studies of the influence of lipid environment on membrane proteins are complex, tedious, and time consuming, which recently boosted the development of computational approaches to this problem. In the case of P2Y12, early numerical studies [23,24] were pushed forward by resolution of the crystallographic structures of the P2Y12 complexed with the full agonist 2-methylthioadenosine-5 -diphosphate (2MeSADP, PDB ID: 4PXZ), with the partial agonist 2-methylthio-adenosine-5 -triphosphate (2MeSATP, PDB ID: 4PY0) [25] and with the antagonist ethyl 6-(4-((benzylsulfonyl)carbamoyl)piperidine-1-yl)-5-cyano-2methylnicotinate (AZD1283, PDB ID: 4NTJ) [25]. These structures differ substantially by the conformation of transmembrane helix 6 (TM6).…”

Section: Introductionmentioning

confidence: 99%

Membrane Environment Modulates Ligand-Binding Propensity of P2Y12 Receptor

et al. 2021

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The binding of natural ligands and synthetic drugs to the P2Y12 receptor is of great interest because of its crucial role in platelets activation and the therapy of arterial thrombosis. Up to now, all computational studies of P2Y12 concentrated on the available crystal structures, while the role of intrinsic protein dynamics and the membrane environment in the functioning of P2Y12 was not clear. In this work, we performed all-atom molecular dynamics simulations of the full-length P2Y12 receptor in three different membrane environments and in two possible conformations derived from available crystal structures. The binding of ticagrelor, its two major metabolites, adenosine diphosphate (ADP) and 2-Methylthioadenosine diphosphate (2MeS-ADP) as agonist, and ethyl 6-[4-(benzylsulfonylcarbamoyl)piperidin-1-yl]-5-cyano-2-methylpyridine-3-carboxylate (AZD1283)as antagonist were assessed systematically by means of ensemble docking. It is shown that the binding of all ligands becomes systematically stronger with the increase of the membrane rigidity. Binding of all ligands to the agonist-bound-like conformations is systematically stronger in comparison to antagonist-bound-likes ones. This is dramatically opposite to the results obtained for static crystal structures. Our results show that accounting for internal protein dynamics, strongly modulated by its lipid environment, is crucial for correct assessment of the ligand binding to P2Y12.

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“…Successive binding of ADP to the Gα i2 -coupled P2Y 12 reduction of intracellular cyclic adenosine-3 0 ,5 0 -monophosphate levels and subsequent amplification of stable platelet aggregation. [10][11][12][13] 8 Antagonism of the P2Y 12 receptor results in inhibition of platelet aggregation and a reduction in occlusive thrombotic events.…”

Section: Introductionmentioning

confidence: 99%

Molecular mechanism of action for reversible P2Y12 antagonists

Cited by 10 publications

References 47 publications

Using ortholog sequence data to predict the functional relevance of mutations in G‐protein‐coupled receptors

Using ortholog sequence data to predict the functional relevance of mutations in G‐protein‐coupled receptors

Membrane Environment Modulates Ligand-Binding Propensity of P2Y12 Receptor

Recent Advances in the Development of P2Y12 Receptor Antagonists as Antiplatelet Agents

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