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TitleCryo-EM structures of orphan GPR21 signaling complexes.
Journal, issue, pagesNat Commun, Vol. 14, Issue 1, Page 216, Year 2023
Publish dateJan 13, 2023
AuthorsXi 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 /
PubMed AbstractGPR21 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.
External linksNat Commun / PubMed:36639690 / PubMed Central
MethodsEM (single particle)
Resolution3.12 - 3.8 Å
Structure data

33480

8hix

EMDB-33480: GPR21_m5_Gs
PDB-8hix: Cryo-EM structure of GPR21_m5_Gs
Method: EM (single particle) / Resolution: 3.12 Å

33481

8hj2

EMDB-33481, PDB-8hj2:
GPR21 wt with G15 complex
Method: EM (single particle) / Resolution: 3.8 Å

33482

8hj0

EMDB-33482, PDB-8hj0:
GPR21(m5) and G15 complex
Method: EM (single particle) / Resolution: 3.12 Å

33483

8hj1

EMDB-33483, PDB-8hj1:
GPR21(wt) and Gs complex
Method: EM (single particle) / Resolution: 3.3 Å

Source
  • homo sapiens (human)
KeywordsSTRUCTURAL PROTEIN / GPCR / Orphan Receptor

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