Molecular insights into ligand recognition and signaling of GPR99/OXGR1

Read the full article See related articles

Listed in

This article is not in any list yet, why not save it to one of your lists.
Log in to save this article

Abstract

GPR99/OXGR1 is a G protein-coupled receptor (GPCR) with two endogenous agonists, the tricarboxylic acid cycle derivative oxoglutarate and the inflammatory lipid mediator leukotriene E4 (LTE 4 ). How GPR99/OXGR1 recognizes two distinct ligands is a biologically important question relevant to therapeutic development due to its established roles in asthma, allergy and inflammation. Here we present cryo-EM structures of GPR99/OXGR1-Gq complex with oxoglutarate and LTE 4 , respectively. The oxoglutarate-bound structure shows a binding pocket surrounded by the transmembrane domains (TM), with a primary site and an accessory site for simultaneous binding of two oxoglutarate molecules for full activation of the receptor. The TM binding pocket, however, is too small to accommodate the “Y” shaped structure of LTE 4 , a cysteinyl leukotriene. Alanine substitution of key residues for oxoglutarate binding had little impact on LTE 4 -induced signaling. An alternative site in between TM3/4/5 just above intracellular loop 2 was identified in the cryo-EM structure of GPR99/OXGR1-Gq complex formed with LTE 4 , but the densities were less well defined. Alanine substitution of amino acids potentially involved in LTE 4 interaction at this site abrogated LTE 4 -induced receptor activation, with no effect on oxoglutarate-induced signaling. Both ligands activated GPR99/OXGR1 primarily through the Gq pathway, but LTE 4 also induced inhibition of cAMP accumulation that was sensitive to pertussis toxin. These findings illustrate the structural basis for GPR99/OXGR1 interaction with oxoglutarate and suggest the presence of a distinct binding site for LTE 4 .

Article activity feed