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http://hdl.handle.net/2445/48359
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DC Field | Value | Language |
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dc.contributor.author | Grosdidier, Solène | - |
dc.contributor.author | Carbó, Laia R. | - |
dc.contributor.author | Buzón Redorta, Víctor | - |
dc.contributor.author | Brooke, Greg | - |
dc.contributor.author | Nguyen, Phuong | - |
dc.contributor.author | Baxter, John D. | - |
dc.contributor.author | Bevan, Charlotte L. | - |
dc.contributor.author | Webb, Paul | - |
dc.contributor.author | Estébanez Perpiñá, Eva | - |
dc.contributor.author | Fernández-Recio, Juan | - |
dc.date.accessioned | 2013-12-09T13:32:31Z | - |
dc.date.available | 2013-12-09T13:32:31Z | - |
dc.date.issued | 2012-07-01 | - |
dc.identifier.issn | 0888-8809 | - |
dc.identifier.uri | http://hdl.handle.net/2445/48359 | - |
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. | - |
dc.format.extent | 13 p. | - |
dc.format.mimetype | application/pdf | - |
dc.language.iso | eng | - |
dc.publisher | Endocrine Society | - |
dc.relation.isformatof | Reproducció del document publicat a: http://dx.doi.org/10.1210/me.2011-1281 | - |
dc.relation.ispartof | Molecular Endocrinology, 2012, vol. 26, num. 7, p. 1078-1090 | - |
dc.relation.uri | http://dx.doi.org/10.1210/me.2011-1281 | - |
dc.rights | (c) Endocrine Society, 2012 | - |
dc.source | Articles publicats en revistes (Bioquímica i Biomedicina Molecular) | - |
dc.subject.classification | Receptors nuclears (Bioquímica) | - |
dc.subject.classification | Càncer de pròstata | - |
dc.subject.other | Nuclear receptors (Biochemistry) | - |
dc.subject.other | 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.identifier.idgrec | 617559 | - |
dc.date.updated | 2013-12-09T13:32:31Z | - |
dc.rights.accessRights | info:eu-repo/semantics/openAccess | - |
dc.identifier.pmid | 22653923 | - |
Appears in Collections: | Articles publicats en revistes (Bioquímica i Biomedicina Molecular) |
Files in This Item:
File | Description | Size | Format | |
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617559.pdf | 2.11 MB | Adobe PDF | View/Open |
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