Mapping the Binding Sites of UDP and Prostaglandin E2 Glyceryl Ester in the Nucleotide Receptor P2Y₆

Abstract

Cyclooxygenase-2 catalyzes the biosynthesis of prostaglandins from arachidonic acid and the biosynthesis of prostaglandin glycerol esters (PG-Gs) from 2-arachidonoylglycerol. PG-Gs are mediators of several biological actions such as macrophage activation, hyperalgesia, synaptic plasticity, and intraocular pressure. Recently, the human UDP receptor P2Y 6 was identified as a target for the prostaglandin E2 glycerol ester (PGE 2 -G).Here, we show that UDP and PGE 2 -G are evolutionary conserved endogenous agonists at vertebrate P2Y 6 orthologs. Using sequence comparison of P2Y 6 orthologs, homology modeling, and ligand docking studies, we proposed several receptor positions participating in agonist binding. Site-directed mutagenesis and functional analysis of these P2Y 6 mutants revealed that both UDP and PGE 2 -G share in parts one ligand-binding site. Thus, the convergent signaling of these two chemically very different agonists has already been manifested in the evolutionary design of the ligand-binding pocket.

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“…The P2Y6 receptor binds UDP preferentially, and its polar residues R103 and R287 interact with the phosphate and glyceryl moieties of the ligand 21 , 22 . The endocytic pathway is known to promote receptor-mediated signaling responses.…”