Cryo-EM structures of orphan GPR21 signaling complexes

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 () and Fei Xu ()
Additional contact information
Xi Lin: ShanghaiTech University
Bo Chen: ShanghaiTech University
Yiran Wu: ShanghaiTech University
Yingqi Han: Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Ao Qi: Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Junyan Wang: Shandong University
Zhao Yang: Shandong University
Xiaohu Wei: ShanghaiTech University
Tingting Zhao: Nanjing University of Chinese Medicine
Lijie Wu: ShanghaiTech University
Xin Xie: Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Jinpeng Sun: Shandong University
Jie Zheng: Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Suwen Zhao: ShanghaiTech University
Fei Xu: ShanghaiTech University

Nature Communications, 2023, vol. 14, issue 1, 1-12

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-35882-w

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