EMD-38183

Single-particle
3.49 Å
EMD-38183 Deposition: 01/12/2023
Map released: 12/02/2025
Last modified: 12/02/2025
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links

EMD-38183

Identification, structure and agonist design of an androgen membrane receptor.

EMD-38183

Single-particle
3.49 Å
EMD-38183 Deposition: 01/12/2023
Map released: 12/02/2025
Last modified: 12/02/2025
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
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
Identification, structure, and agonist design of an androgen membrane receptor.
PUBMED: 39884271
DOI: doi:10.1016/j.cell.2025.01.006
ISSN: 1097-4172
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.