8X9T

Identification, structure and agonist design of an androgen membrane receptor

Summary for 8X9T

• Entry DOI: 10.2210/pdb8x9t/pdb
• EMDB information: 38184
• Descriptor: Gs protein alpha subunit, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (6 entities in total)
• Functional Keywords: adhesion gpcr, gpr133, membrane protein
• Biological source: Bos taurus; More
• Total number of polymer chains: 5
• Total formula weight: 182421.25

Authors

Ping, Y.Q.,Yang, Z. (deposition date: 2023-12-01, release date: 2025-02-12, Last modification date: 2025-04-09)

Primary citation

Yang, Z.,Ping, Y.Q.,Wang, M.W.,Zhang, C.,Zhou, S.H.,Xi, Y.T.,Zhu, K.K.,Ding, W.,Zhang, Q.Y.,Song, Z.C.,Zhao, R.J.,He, Z.L.,Wang, M.X.,Qi, L.,Ullmann, C.,Ricken, A.,Schoneberg, T.,Gan, Z.J.,Yu, X.,Xiao, P.,Yi, F.,Liebscher, I.,Sun, J.P.
Identification, structure, and agonist design of an androgen membrane receptor.
Cell, 188:1589-, 2025

PubMed Abstract: Androgens, such as 5α-dihydrotestosterone (5α-DHT), regulate numerous functions by binding to nuclear androgen receptors (ARs) and potential unknown membrane receptors. Here, we report that the androgen 5α-DHT activates membrane receptor GPR133 in muscle cells, thereby increasing intracellular cyclic AMP (cAMP) levels and enhancing muscle strength. Further cryoelectron microscopy (cryo-EM) structural analysis of GPR133-Gs in complex with 5α-DHT or its derivative methenolone (MET) reveals the structural basis for androgen recognition. Notably, the presence of the "Φ(F/L)-F-W" and the "F××N/D" motifs, which recognize the hydrophobic steroid core and polar groups, respectively, are common in adhesion GPCRs (aGPCRs), suggesting that many aGPCRs may recognize different steroid hormones. Finally, we exploited in silico screening methods to identify a small molecule, AP503, which activates GPR133 and separates the beneficial muscle-strengthening effects from side effects mediated by AR. Thus, GPR133 represents an androgen membrane receptor that contributes to normal androgen physiology and has important therapeutic potentials.

PubMed: 39884271
DOI: 10.1016/j.cell.2025.01.006

Experimental method

ELECTRON MICROSCOPY (2.75 Å)