EMD-37356

Single-particle
2.89 Å
EMD-37356 Deposition: 04/09/2023
Map released: 03/01/2024
Last modified: 30/10/2024
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links

EMD-37356

Cryo-EM structure of the GPR101-Gs complex

EMD-37356

Single-particle
2.89 Å
EMD-37356 Deposition: 04/09/2023
Map released: 03/01/2024
Last modified: 30/10/2024
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Sample Organism: Homo sapiens
Sample: Cryo-EM structure of the GPR101-Gs complex
Fitted models: 8w8q (Avg. Q-score: 0.564)

Deposition Authors: Sun JP , Gao N , Yu X , Wang GP, Yang F, Wang JY, Yang Z, Guan Y
Structure of GPR101-Gs enables identification of ligands with rejuvenating potential.
PUBMED: 37945893
DOI: doi:10.1038/s41589-023-01456-6
ISSN: 1552-4469
Abstract:
GPR101 is an orphan G protein-coupled receptor actively participating in energy homeostasis. Here we report the cryo-electron microscopy structure of GPR101 constitutively coupled to Gs heterotrimer, which reveals unique features of GPR101, including the interaction of extracellular loop 2 within the 7TM bundle, a hydrophobic chain packing-mediated activation mechanism and the structural basis of disease-related mutants. Importantly, a side pocket is identified in GPR101 that facilitates in silico screening to identify four small-molecule agonists, including AA-14. The structure of AA-14-GPR101-Gs provides direct evidence of the AA-14 binding at the side pocket. Functionally, AA-14 partially restores the functions of GH/IGF-1 axis and exhibits several rejuvenating effects in wild-type mice, which are abrogated in Gpr101-deficient mice. In summary, we provide a structural basis for the constitutive activity of GPR101. The structure-facilitated identification of GPR101 agonists and functional analysis suggest that targeting this orphan receptor has rejuvenating potential.