8hj0 Citations

Cryo-EM structures of orphan GPR21 signaling complexes.

OpenAccess logo Nat Commun 14 216 (2023)
Related entries: 8hix, 8hj1, 8hj2

Cited: 9 times
EuropePMC logo PMID: 36639690

Abstract

GPR21 is a class-A orphan G protein-coupled receptor (GPCR) and a potential therapeutic target for type 2 diabetes and other metabolic disorders. This receptor shows high basal activity in coupling to multiple G proteins in the absence of any known endogenous agonist or synthetic ligand. Here, we present the structures of ligand-free human GPR21 bound to heterotrimeric miniGs and miniG15 proteins, respectively. We identified an agonist-like motif in extracellular loop 2 (ECL2) that occupies the orthosteric pocket and promotes receptor activation. A side pocket that may be employed as a new ligand binding site was also uncovered. Remarkably, G protein binding is accommodated by a flexible cytoplasmic portion of transmembrane helix 6 (TM6) which adopts little or undetectable outward movement. These findings will enable the design of modulators for GPR21 for understanding its signal transduction and exploring opportunity for deorphanization.

Reviews citing this publication (3)

  1. Orphan G Protein-Coupled Receptor GPR37 as an Emerging Therapeutic Target. Bolinger AA, Frazier A, La JH, Allen JA, Zhou J. ACS Chem Neurosci 14 3318-3334 (2023)
  2. Structure, function and drug discovery of GPCR signaling. Cheng L, Xia F, Li Z, Shen C, Yang Z, Hou H, Sun S, Feng Y, Yong X, Tian X, Qin H, Yan W, Shao Z. Mol Biomed 4 46 (2023)
  3. Bridging structural and cell biology with cryo-electron microscopy. Nogales E, Mahamid J. Nature 628 47-56 (2024)

Articles citing this publication (6)