EMD-38183
Identification, structure and agonist design of an androgen membrane receptor.
EMD-38183
Single-particle3.49 Å
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Map released: 12/02/2025
Last modified: 12/02/2025
Sample Organism:
Bos taurus,
Rattus norvegicus,
Homo sapiens
Sample: Complex of GPR133 with agonist and G protein trime
Fitted models: 8x9s
Deposition Authors: Ping YQ, Yang Z
Sample: Complex of GPR133 with agonist and G protein trime
Fitted models: 8x9s
Deposition Authors: Ping YQ, Yang Z
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
(2025) Cell
(2025) Cell
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)2.64-F3.40-W6.53" and the "F7.42××N/D7.46" 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.
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)2.64-F3.40-W6.53" and the "F7.42××N/D7.46" 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.