Grosdidier, Solène and Carbó, Laia R and Buzón, Víctor and Brooke, Greg and Nguyen, Phuong and Baxter, John D and Bevan, Charlotte and Webb, Paul and Estébanez-Perpiñá, Eva and Fernández-Recio, Juan (2012) Allosteric Conversation in the Androgen Receptor Ligand-Binding Domain Surfaces. Molecular Endocrinology, 26 (7). pp. 1078-1090. DOI https://doi.org/10.1210/me.2011-1281
Grosdidier, Solène and Carbó, Laia R and Buzón, Víctor and Brooke, Greg and Nguyen, Phuong and Baxter, John D and Bevan, Charlotte and Webb, Paul and Estébanez-Perpiñá, Eva and Fernández-Recio, Juan (2012) Allosteric Conversation in the Androgen Receptor Ligand-Binding Domain Surfaces. Molecular Endocrinology, 26 (7). pp. 1078-1090. DOI https://doi.org/10.1210/me.2011-1281
Grosdidier, Solène and Carbó, Laia R and Buzón, Víctor and Brooke, Greg and Nguyen, Phuong and Baxter, John D and Bevan, Charlotte and Webb, Paul and Estébanez-Perpiñá, Eva and Fernández-Recio, Juan (2012) Allosteric Conversation in the Androgen Receptor Ligand-Binding Domain Surfaces. Molecular Endocrinology, 26 (7). pp. 1078-1090. DOI https://doi.org/10.1210/me.2011-1281
Abstract
Androgen receptor (AR) is a major therapeutic target that plays pivotal roles in prostate cancer (PCa) and androgen insensitivity syndromes. Wepreviously 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. © 2012 by The Endocrie Society.
Item Type: | Article |
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Uncontrolled Keywords: | Cell Line, Tumor; Hela Cells; Humans; Prostatic Neoplasms; Androgen-Insensitivity Syndrome; Receptors, Androgen; Ligands; Binding Sites; Protein Conformation; Protein Structure, Tertiary; Protein Binding; Protein Folding; Mutation; Models, Molecular; Male; Protein Interaction Domains and Motifs; Molecular Dynamics Simulation |
Subjects: | R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer) |
Divisions: | Faculty of Science and Health Faculty of Science and Health > Life Sciences, School of |
SWORD Depositor: | Unnamed user with email elements@essex.ac.uk |
Depositing User: | Unnamed user with email elements@essex.ac.uk |
Date Deposited: | 04 Dec 2013 10:23 |
Last Modified: | 30 Oct 2024 19:21 |
URI: | http://repository.essex.ac.uk/id/eprint/8307 |
Available files
Filename: 1078.full.pdf