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 Å resolution; 1 Å=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 π-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 Pγ (the γ-phosphate of the triphosphate chain of ATP) and Met310 interacts with the adenine moiety.
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Research Article|
June 27 2007
Structure and ligand-binding site characteristics of the human P2Y11 nucleotide receptor deduced from computational modelling and mutational analysis
Jacques Zylberg;
Jacques Zylberg
1
*Gonda-Goldschmied Medical Research Center, Department of Chemistry, Bar-Ilan University, Ramat-Gan 52900, Israel
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Denise Ecke;
Denise Ecke
1
†Institut für Neurobiochemie, Medizinische Fakultät, Otto-von-Guericke-Universität Magdeburg, Leipziger Strasse 44, 39120 Magdeburg, Germany
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Bilha Fischer;
Bilha Fischer
2
*Gonda-Goldschmied Medical Research Center, Department of Chemistry, Bar-Ilan University, Ramat-Gan 52900, Israel
2Correspondence may be addressed to either of the authors (email bfischer@mail.biu.ac.il or georg.reiser@med.ovgu.de).
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Georg Reiser
Georg Reiser
2
†Institut für Neurobiochemie, Medizinische Fakultät, Otto-von-Guericke-Universität Magdeburg, Leipziger Strasse 44, 39120 Magdeburg, Germany
2Correspondence may be addressed to either of the authors (email bfischer@mail.biu.ac.il or georg.reiser@med.ovgu.de).
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Publisher: Portland Press Ltd
Received:
November 20 2006
Revision Received:
February 13 2007
Accepted:
March 06 2007
Accepted Manuscript online:
March 06 2007
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2007 Biochemical Society
2007
Biochem J (2007) 405 (2): 277–286.
Article history
Received:
November 20 2006
Revision Received:
February 13 2007
Accepted:
March 06 2007
Accepted Manuscript online:
March 06 2007
Citation
Jacques Zylberg, Denise Ecke, Bilha Fischer, Georg Reiser; Structure and ligand-binding site characteristics of the human P2Y11 nucleotide receptor deduced from computational modelling and mutational analysis. Biochem J 15 July 2007; 405 (2): 277–286. doi: https://doi.org/10.1042/BJ20061728
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