2026-04-03T19:19:24Zhttps://recercat.cat/oai/request
oai:recercat.cat:2445/483592025-12-04T21:15:17Zcom_2072_1057col_2072_478781col_2072_478917
RECERCAT author Grosdidier, Solène author Carbó, Laia R. author Buzón Redorta, Víctor author Brooke, Greg author Nguyen, Phuong author Baxter, John D. author Bevan, Charlotte L. author Webb, Paul author Estébanez Perpiñá, Eva author Fernández-Recio, Juan 2013-12-09T13:32:31Z2013-12-09T13:32:31Z2012-07-012013-12-09T13:32:31Z Androgen receptor (AR) is a major therapeutic target that plays pivotal roles in prostate cancer (PCa) and androgen insensitivity syndromes. We previously proposed that compounds recruited to ligand-binding domain (LBD) surfaces could regulate AR activity in hormone-refractory PCa and discovered several surface modulators of AR function. Surprisingly, the most effective compounds bound preferentially to a surface of unknown function [binding function 3 (BF-3)] instead of the coactivator-binding site [activation function 2 (AF-2)]. Different BF-3 mutations have been identified in PCa or androgen insensitivity syndrome patients, and they can strongly affect AR activity. Further, comparison of AR x-ray structures with and without bound ligands at BF-3 and AF-2 showed structural coupling between both pockets. Here, we combine experimental evidence and molecular dynamic simulations to investigate whether BF-3 mutations affect AR LBD function and dynamics possibly via allosteric conversation between surface sites. Our data indicate that AF-2 conformation is indeed closely coupled to BF-3 and provide mechanistic proof of their structural interconnection. BF-3 mutations may function as allosteric elicitors, probably shifting the AR LBD conformational ensemble toward conformations that alter AF-2 propensity to reorganize into subpockets that accommodate N-terminal domain and coactivator peptides. The induced conformation may result in either increased or decreased AR activity. Activating BF-3 mutations also favor the formation of another pocket (BF-4) in the vicinity of AF-2 and BF-3, which we also previously identified as a hot spot for a small compound. We discuss the possibility that BF-3 may be a protein-docking site that binds to the N-terminal domain and corepressors. AR surface sites are attractive pharmacological targets to develop allosteric modulators that might be alternative lead compounds for drug design. (c) Endocrine Society, 2012 info:eu-repo/semantics/openAccess Receptors nuclears (Bioquímica) Càncer de pròstata Nuclear receptors (Biochemistry) Prostate cancer Allosteric conversation in the androgen receptor ligand-binding domain surfaces info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion