National Natural Science Foundation of China (NSFC)
China
Citation
Journal: Nat Commun / Year: 2023 Title: Cryo-EM structures of orphan GPR21 signaling complexes. Authors: Xi Lin / Bo Chen / Yiran Wu / Yingqi Han / Ao Qi / Junyan Wang / Zhao Yang / Xiaohu Wei / Tingting Zhao / Lijie Wu / Xin Xie / Jinpeng Sun / Jie Zheng / Suwen Zhao / Fei Xu / 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 ...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.
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