dc.contributor |
Universitat de Barcelona |
dc.contributor.author |
Grosdidier, Solène |
dc.contributor.author |
Carbó, Laia R. |
dc.contributor.author |
Buzón Redorta, Victor |
dc.contributor.author |
Brooke, Greg |
dc.contributor.author |
Nguyen, Phuong |
dc.contributor.author |
Baxter, John D. |
dc.contributor.author |
Bevan, Charlotte |
dc.contributor.author |
Webb, Paul |
dc.contributor.author |
Estébanez Perpiñá, Eva |
dc.contributor.author |
Fernández-Recio, Juan |
dc.date |
2013-12-09T13:32:31Z |
dc.date |
2013-12-09T13:32:31Z |
dc.date |
2012-07-01 |
dc.date |
2013-12-09T13:32:31Z |
dc.identifier.citation |
0888-8809 |
dc.identifier.citation |
617559 |
dc.identifier.uri |
http://hdl.handle.net/2445/48359 |
dc.format |
13 p. |
dc.format |
application/pdf |
dc.language.iso |
eng |
dc.publisher |
Endocrine Society |
dc.relation |
Reproducció del document publicat a: http://dx.doi.org/10.1210/me.2011-1281 |
dc.relation |
Molecular Endocrinology, 2012, vol. 26, num. 7, p. 1078-1090 |
dc.relation |
http://dx.doi.org/10.1210/me.2011-1281 |
dc.rights |
(c) Endocrine Society, 2012 |
dc.rights |
info:eu-repo/semantics/openAccess |
dc.subject |
Receptors nuclears (Bioquímica) |
dc.subject |
Càncer de pròstata |
dc.subject |
Nuclear receptors (Biochemistry) |
dc.subject |
Prostate cancer |
dc.title |
Allosteric conversation in the androgen receptor ligand-binding domain surfaces |
dc.type |
info:eu-repo/semantics/article |
dc.type |
info:eu-repo/semantics/publishedVersion |
dc.description.abstract |
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. |