Journal of Computer-Aided Molecular Design

, Volume 20, Issue 7, pp 417–426

Defining the nucleotide binding sites of P2Y receptors using rhodopsin-based homology modeling

  • Andrei A. Ivanov
  • Stefano Costanzi
  • Kenneth A. Jacobson
Original Paper

DOI: 10.1007/s10822-006-9054-2

Cite this article as:
Ivanov, A.A., Costanzi, S. & Jacobson, K.A. J Comput Aided Mol Des (2006) 20: 417. doi:10.1007/s10822-006-9054-2

Abstract

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.

Keywords

GPCRsP2Y receptorsHomology modelingBinding modeLigand recognitionNucleotides

Copyright information

© Springer Science+Business Media B.V. 2006

Authors and Affiliations

  • Andrei A. Ivanov
    • 1
  • Stefano Costanzi
    • 2
  • Kenneth A. Jacobson
    • 1
  1. 1.Molecular Recognition Section, Laboratory of Bioorganic ChemistryNational Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of HealthBethesdaUSA
  2. 2.Computational Chemistry Core LaboratoryNational Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of HealthBethesdaUSA