ArticleMolecular endocrinology (Baltimore, Md.)2012
Allosteric conversation in the androgen receptor ligand-binding domain surfaces.
Article in Molecular endocrinology (Baltimore, Md.), 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
23 citing papers in PubMed, 69 citations in OpenAlex.
- Anabolic-Androgenic Steroids Revisited: Structural Biology, Receptor Signaling, and Mechanisms of Anabolic-Androgenic Dissociation.International journal of molecular sciences · 2026Review
- Nuclear Receptors in Bladder Cancer: Insights into miRNA-Mediated Regulation and Potential Therapeutic Implications.International journal of molecular sciences · 2025Review
- Review
- Discovery of Novel Anti-Resistance AR Antagonists Guided by Funnel Metadynamics Simulation.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Characterization of allosteric modulators that disrupt androgen receptor co-activator protein-protein interactions to alter transactivation-Drug leads for metastatic castration resistant prostate cancer.SLAS discovery : advancing life sciences R & D · 2023Article
- A hotspot for posttranslational modifications on the androgen receptor dimer interface drives pathology and anti-androgen resistance.Science advances · 2023Article
- Review
- A novel chemo-phenotypic method identifies mixtures of salpn, vitamin D3, and pesticides involved in the development of colorectal and pancreatic cancer.Ecotoxicology and environmental safety · 2022Article
- The T850D Phosphomimetic Mutation in the Androgen Receptor Ligand Binding Domain Enhances Recruitment at Activation Function 2.International journal of molecular sciences · 2022Article
- Structural Dynamics of Agonist and Antagonist Binding to the Androgen Receptor.The journal of physical chemistry. B · 2019Article
- Androgen Receptor Dependence.Advances in experimental medicine and biology · 2019Review
- Molecular Dynamics Simulations Revealed the Regulation of Ligands to the Interactions between Androgen Receptor and Its Coactivator.Journal of chemical information and modeling · 2018Article
- Endocrine Disrupting Chemicals Mediated through Binding Androgen Receptor Are Associated with Diabetes Mellitus.International journal of environmental research and public health · 2017Review
- Structure of the homodimeric androgen receptor ligand-binding domain.Nature communications · 2017Article
- Article
- Targeting Binding Function-3 of the Androgen Receptor Blocks Its Co-Chaperone Interactions, Nuclear Translocation, and Activation.Molecular cancer therapeutics · 2016Article
- Similarities and Distinctions in Actions of Surface-Directed and Classic Androgen Receptor Antagonists.PloS one · 2015Article
- Androgen receptor: structure, role in prostate cancer and drug discovery.Acta pharmacologica Sinica · 2015Review
- An alternate binding site for PPARγ ligands.Nature communications · 2014Article
- Coregulator control of androgen receptor action by a novel nuclear receptor-binding motif.The Journal of biological chemistry · 2014Article
Corrections and comments
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Authors and funding
10 authors at 5 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.