2026-04-17T06:39:39Zhttps://recercat.cat/oai/request

oai:recercat.cat:2445/1985872025-12-04T20:57:26Zcom_2072_1057col_2072_478781col_2072_478796col_2072_478916col_2072_478917

00925njm 22002777a 4500 dc Alegre-Martí, Andrea author Jiménez Panizo, Alba author Martínez Tébar, Adrián author Poulard, Coralie author Peralta Moreno, María Nuria author Abella, Montserrat author Antón, Rosa author Chiñas, Marcos author Eckhard, Ulrich author Piulats, Josep M. author Rojas, Ana M. author Fernández Recio, Juan author Rubio Martínez, Jaime author Le Romancer, Muriel author Aytés Meneses, Álvaro author Fuentes-Prior, Pablo author Estébanez Perpiñá, Eva author 2023-05-29T17:58:40Z 2023-05-29T17:58:40Z 2022-12-05 2023-05-29T17:58:40Z Mutations of the androgen receptor (AR) associated with prostate cancer and androgen insensitivity syndrome may profoundly influence its structure, protein interaction network, and binding to chromatin, resulting in altered transcription signatures and drug responses. Current structural information fails to explain the effect of pathological mutations on AR structure-function relationship. Here, we have thoroughly studied the effects of selected mutations that span the complete dimer interface of AR ligand-binding domain (AR-LBD) using x-ray crystallography in combination with in vitro, in silico, and cell-based assays. We show that these variants alter AR-dependent transcription and responses to anti-androgens by inducing a previously undescribed allosteric switch in the AR-LBD that increases exposure of a major methylation target, Arg761. We also corroborate the relevance of residues Arg761 and Tyr764 for AR dimerization and function. Together, our results reveal allosteric coupling of AR dimerization and posttranslational modifications as a disease mechanism with implications for precision medicine. Càncer de pròstata Fixació de proteïnes Mutació (Biologia) Prostate cancer Protein binding Mutation (Biology) A hotspot for posttranslational modifications on the androgen receptor dimer interface drives pathology and anti-androgen resistance