9iv1
Identification, structure and agonist design of an androgen membrane receptor.
Structural highlights
FunctionAGRD1_HUMAN Orphan receptor. Signals via G(s)-alpha family of G-proteins (PubMed:22025619, PubMed:22575658). Has protumorigenic function especially in glioblastoma (PubMed:27775701).[1] [2] [3] Publication Abstract from PubMedAndrogens, such as 5alpha-dihydrotestosterone (5alpha-DHT), regulate numerous functions by binding to nuclear androgen receptors (ARs) and potential unknown membrane receptors. Here, we report that the androgen 5alpha-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 5alpha-DHT or its derivative methenolone (MET) reveals the structural basis for androgen recognition. Notably, the presence of the "Phi(F/L)(2.64)-F(3.40)-W(6.53)" and the "F(7.42)xxN/D(7.46)" 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. Identification, structure, and agonist design of an androgen membrane receptor.,Yang Z, Ping YQ, Wang MW, Zhang C, Zhou SH, Xi YT, Zhu KK, Ding W, Zhang QY, Song ZC, Zhao RJ, He ZL, Wang MX, Qi L, Ullmann C, Ricken A, Schoneberg T, Gan ZJ, Yu X, Xiao P, Yi F, Liebscher I, Sun JP Cell. 2025 Jan 23:S0092-8674(25)00035-2. doi: 10.1016/j.cell.2025.01.006. PMID:39884271[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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