8W8S
Cryo-EM structure of the AA14-bound GPR101 complex
Summary for 8W8S
| Entry DOI | 10.2210/pdb8w8s/pdb |
| EMDB information | 37358 |
| Descriptor | Probable G-protein coupled receptor 101, 1-(4-methylpyridin-2-yl)-3-[3-(trifluoromethyl)phenyl]thiourea (2 entities in total) |
| Functional Keywords | gpcr, orphan receptor, gpr101, constitutive activity, cryo-em, structural protein, membrane protein |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 57397.58 |
| 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: 2024-10-16) |
| 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 Cited by 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: 37945893DOI: 10.1038/s41589-023-01456-6 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.3 Å) |
Structure validation
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