ArticleThe Biochemical journal2007
Structure and ligand-binding site characteristics of the human P2Y11 nucleotide receptor deduced from computational modelling and mutational analysis.
Article in The Biochemical journal, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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16 citing papers in PubMed, 51 citations in OpenAlex.
- Drug-like Antagonists of P2Y Receptor Subtypes: An Update.Journal of medicinal chemistry · 2025Review
- Extracellular purines in lung endothelial permeability and pulmonary diseases.Frontiers in physiology · 2024Review
- P2Y Purinergic Receptors, Endothelial Dysfunction, and Cardiovascular Diseases.International journal of molecular sciences · 2020Review
- Molecular Modeling Applied to the Discovery of New Lead Compounds for P2 Receptors Based on Natural Sources.Frontiers in pharmacology · 2020Review
- Human P2YFrontiers in immunology · 2018Article
- Nucleotides Acting at P2Y Receptors: Connecting Structure and Function.Molecular pharmacology · 2015Review
- Highly potent and selective ectonucleotide pyrophosphatase/phosphodiesterase I inhibitors based on an adenosine 5'-(α or γ)-thio-(α,β- or β,γ)-methylenetriphosphate scaffold.Journal of medicinal chemistry · 2014Article
- Probing GPCR structure: adenosine and P2Y nucleotide receptors.Methods in enzymology · 2013Article
- Molecular Structure of P2Y Receptors: Mutagenesis, Modeling, and Chemical Probes.Wiley interdisciplinary reviews. Membrane transport and signaling · 2012Article
- G protein-coupled adenosine (P1) and P2Y receptors: ligand design and receptor interactions.Purinergic signalling · 2012Review
- Virtual ligand screening against comparative protein structure models.Methods in molecular biology (Clifton, N.J.) · 2012Article
- Deconstructing nucleotide binding activity of the Mdm2 RING domain.Nucleic acids research · 2010Article
- P2Y nucleotide receptors: promise of therapeutic applications.Drug discovery today · 2010Review
- Molecular docking screens using comparative models of proteins.Journal of chemical information and modeling · 2009Article
- Toward the three-dimensional structure and lysophosphatidic acid binding characteristics of the LPA(4)/p2y(9)/GPR23 receptor: a homology modeling study.Journal of molecular graphics & modelling · 2009Article
- Diastereoselectivity of the P2Y11 nucleotide receptor: mutational analysis.British journal of pharmacology · 2008Article
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Authors and funding
4 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The P2Y11-R (P2Y11 receptor) is a less explored drug target. We computed an hP2Y11-R (human P2Y11) homology model with two templates, bovine-rhodopsin (2.6 A resolution; 1 A=0.1 nm) and a hP2Y1-ATP complex model. The hP2Y11-R model was refined using molecular dynamics calculations and validated by virtual screening methods, with an enrichment factor of 5. Furthermore, mutational analyses of Arg106, Glu186, Arg268, Arg307 and Ala313 confirmed the adequacy of our hP2Y11-R model and the computed ligand recognition mode. The E186A and R268A mutants reduced the potency of ATP by one and three orders of magnitude respectively. The R106A and R307A mutants were functionally inactive. We propose that residues Arg106, Arg268, Arg307 and Glu186 are involved in ionic interactions with the phosphate moiety of ATP. Arg307 is possibly also H-bonded to N6 of ATP via the backbone carbonyl. Activity of ATP at the F109I mutant revealed that the proposed p-stacking of Phe109 with the adenine ring is a minor interaction. The mutation A313N, which is part of a hydrophobic pocket in the vicinity of the ATP C-2 position, partially explains the high activity of 2-MeS-ATP at P2Y1-R as compared with the negligible activity at the P2Y11-R. Inactivity of ATP at the Y261A mutant implies that Tyr261 acts as a molecular switch, as in other G-protein-coupled receptors. Moreover, analysis of cAMP responses seen with the mutants showed that the efficacy of coupling of the P2Y11-R with Gs is more variable than coupling with Gq. Our model also indicates that Ser206 forms an H-bond with Pgamma (the gamma-phosphate of the triphosphate chain of ATP) and Met310 interacts with the adenine moiety.
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