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First published on January 4, 2005; DOI: 10.1124/mol.104.010108

0026-895X/05/6704-1078-1088$20.00
Mol Pharmacol 67:1078-1088, 2005

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Original Article

Molecular Determinants of the Agonist Binding Domain of a P2X Receptor Channel

Zonghe Yan, Zhaodong Liang, Melanija Tomic, Tomas Obsil, and Stanko S. Stojilkovic

Section on Cellular Signaling, Endocrinology and Reproduction Research Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland (Z.Y., Z.L., M.T., S.S.S.); and Department of Physical and Macromolecular Chemistry, Faculty of Science, Charles University, Prague, Czech Republic (T.O.)

Abstract

P2 purinergic receptor channel receptors (P2XRs) are a family of ligand-gated cation channels composed of two transmembrane domains, N and C termini located intracellularly, and a large extracellular loop containing the ATP binding domain. To identify regions important for binding and gating, previous experimental work was focused on mutagenesis of conserved ectodomain residues. Here, we used the known sequence and secondary structure similarities between the Lys180-Lys326 ectodomain region of P2X4 and the class II aminoacyl-tRNA synthetases as a guide to generate a three-dimensional model of the receptor-binding site and to design mutants. The interplay between homology modeling and site-directed mutagenesis suggested that Asp280 residue of P2X4R coordinates ATP binding via the magnesium ion, Phe230 residue coordinates the binding of the adenine ring of ATP, and Lys190, His286, and Arg278 residues coordinate the actions of negatively charged {alpha}-, {beta}-, and {gamma}-phosphate groups, respectively. Until the crystal structure of the channel is solved, this model could provide a useful approach for future studies on the identification of ATP binding domain and gating of P2XRs.

Received December 7, 2004; accepted January 4, 2005

Address correspondence to: Dr. Stanko S. Stojilkovic, ERRB/NICHD, Building 49, Room 6A-36, 49 Convent Drive, Bethesda, MD 20892-4510. E-mail: stankos{at}helix.nih.gov




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