8W8R

Cryo-EM structure of the AA-14-bound GPR101-Gs complex

Summary for 8W8R

• Entry DOI: 10.2210/pdb8w8r/pdb
• EMDB information: 37357
• Descriptor: Guanine nucleotide-binding protein G(i) subunit alpha-1,Guanine nucleotide-binding protein G(s) subunit, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Probable G-protein coupled receptor 101, ... (6 entities in total)
• Functional Keywords: gpcr, orphan receptor, gpr101, constitutive activity, cryo-em, structural protein, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 173576.48

Authors

Sun, J.P.,Yu, X.,Gao, N.,Yang, F.,Wang, J.Y.,Yang, Z.,Guan, Y.,Wang, G.P. (deposition date: 2023-09-04, release date: 2024-01-03, Last modification date: 2024-04-10)

Primary citation

Yang, Z.,Wang, J.Y.,Yang, F.,Zhu, K.K.,Wang, G.P.,Guan, Y.,Ning, S.L.,Lu, Y.,Li, Y.,Zhang, C.,Zheng, Y.,Zhou, S.H.,Wang, X.W.,Wang, M.W.,Xiao, P.,Yi, F.,Zhang, C.,Zhang, P.J.,Xu, F.,Liu, B.H.,Zhang, H.,Yu, X.,Gao, N.,Sun, J.P.
Structure of GPR101-Gs enables identification of ligands with rejuvenating potential.
Nat.Chem.Biol., 20:484-492, 2024

PubMed 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.

PubMed: 37945893
DOI: 10.1038/s41589-023-01456-6

Experimental method

ELECTRON MICROSCOPY (3.3 Å)