Defining the nucleotide binding sites of P2Y receptors using rhodopsin-based homology modeling
- 144 Downloads
Ongoing efforts to model P2Y receptors for extracellular nucleotides, i.e., endogenous ADP, ATP, UDP, UTP, and UDP-glucose, were summarized and correlated for the eight known subtypes. The rhodopsin-based homology modeling of the P2Y receptors is supported by a growing body of site-directed mutagenesis data, mainly for P2Y1 receptors. By comparing molecular models of the P2Y receptors, it was concluded that nucleotide binding could occur in the upper part of the helical bundle, with the ribose moiety accommodated between transmembrane domain (TM) 3 and TM7. The nucleobase was oriented towards TM1, TM2, and TM7, in the direction of the extracellular side of the receptor. The phosphate chain was oriented towards TM6, in the direction of the extracellular loops (ELs), and was coordinated by three critical cationic residues. In particular, in the P2Y1, P2Y2, P2Y4, and P2Y6 receptors the nucleotide ligands had very similar positions. ADP in the P2Y12 receptor was located deeper inside the receptor in comparison to other subtypes, and the uridine moiety of UDP-glucose in the P2Y14 receptor was located even deeper and shifted toward TM7. In general, these findings are in agreement with the proposed binding site of small molecules to other class A GPCRs.
KeywordsGPCRs P2Y receptors Homology modeling Binding mode Ligand recognition Nucleotides
Unable to display preview. Download preview PDF.
We acknowledge support from the Intramural Research Program of the NIH, National Institute of Diabetes and Digestive and Kidney Diseases. We thank Prof. Christa Müller and Prof. Ivan von Kügelgen (Univ. of Bonn, Germany) and Prof. T. K. Harden (Univ. of North Carolina) for helpful discussion.
- 1.Abbracchio, MP, Burnstock, G, Boeynaems, JM, Barnard, EA, Boyer, JL, Kennedy, C, Fumagalli, M, King, BF, Gachet, C, Jacobson, KA, Weisman, GA. International Union of Pharmacology. Update of the P2Y G protein-coupled nucleotide receptors: from molecular mechanisms and pathophysiology to therapy. Pharmacol Rev (in press)Google Scholar
- 4.Van Rhee AM, Fischer B, van Galen PJM, Jacobson KA (1995) Modelling the P2Y purinoceptor using rhodopsin as template. Drug Des Discov 13:133Google Scholar
- 7.Jiang Q, Guo D, Lee BX, van Rhee AM, Kim YC, Nicholas RA, Schachter J, Harden TK, Jacobson KA (1997) A mutational analysis of residues essential for ligand recognition at the human P2Y1 receptor. Mol Pharmacol 52:499Google Scholar
- 12.Nandanan E, Jang SY, Moro S, Kim H, Siddiqui MA, Russ P, Marquez VE, Busson R, Herdewijn P, Harden TK, Boyer JL, Jacobson KA (2000) Synthesis, biological activity, and molecular modeling of ribose-modified adenosine bisphosphate analogues as P2Y1 receptor ligands. J Med Chem 43:829CrossRefGoogle Scholar
- 18.Besada P, Shin DH, Costanzi S, Ko HJ, Mathé C, Gagneron J, Gossselin G, Maddileti S, Harden TK, Jacobson KA (2006) Structure activity relationship of uridine 5′-diphosphate analogues at the human P2Y6 receptor. J Med Chem (in press)Google Scholar
- 19.Ivanov AA, Jacobson KA. Molecular dynamics simulation of the human P2Y14 receptor and study of ligand–receptor interactions, 231st Am. Chem. Soc. National Meeting, Atlanta, GA, March 26–30 (2006) Abstract COMP 217Google Scholar
- 22.Mohamadi FN, Richards GJ, Guida WC, Liskamp R, Lipton M, Caufield C, Chang G, Hendrickson T, Still WC MacroModel––an integrated software Google Scholar
- 23.El-Tayeb A, Qi A, Müller CE (2006) Synthesis and structure-activity relationships of base-modified UDP and UTP analogues at the human P2Y2, P2Y4, and P2Y6 receptors. Purinergic Signalling 2:304Google Scholar
- 24.Hoffmann K, Algaier I, von Kügelgen I (2006) Evidence for the involvement of basic amino acid residues in transmembrane regions 6 and 7 of the human platelet P2Y12-receptor in ligand recognition. Purinergic Signalling 2:199Google Scholar