ArticleProtein science : a publication of the Protein Society2022
Topological dynamics of an intrinsically disordered N-terminal domain of the human androgen receptor.
Article in Protein science : a publication of the Protein Society, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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21 citing papers in PubMed, 30 citations in OpenAlex.
- Developing a Fluorescence-Based High-Throughput Screening Method for Natural Product Fractions to Identify Inhibitors of AR-V7 for Castration-Resistant Prostate Cancer.Pharmaceutics · 2026Article
- A Spatiotemporal Atlas of the Androgen Receptor Proximal Interactome.bioRxiv : the preprint server for biology · 2026Article
- A Computational and In Vitro Appraisal of Ostarine to Target Androgen Receptor in Glioma C6 Cells.Cell biochemistry and biophysics · 2025Article
- Molecular analysis of androgen receptor splice variant AR-V3 reveals eminent ambiguity regarding activity and clinical utility.Cancer cell international · 2025Article
- In Silico discovery of novel androgen receptor inhibitors for prostate cancer therapy using virtual screening, molecular docking, and molecular dynamics simulations.Scientific reports · 2025Article
- The evolution of eukaryotic linear motifs governing the function of androgen receptor from fish to Homo sapiens.Nucleic acids research · 2025Article
- Polyglutamine expansion induced dynamic misfolding of androgen receptor.Protein science : a publication of the Protein Society · 2025Article
- Molecular pathogenesis, diagnosis, and management challenges in complete androgen insensitivity syndrome.Frontiers in endocrinology · 2025Review
- Ion mobility mass spectrometry unveils conformational effects of drug lead EPI-001 on the intrinsically disordered N-terminal domain of the androgen receptor.Protein science : a publication of the Protein Society · 2025Article
- The androgen receptor amino-terminal domain: structure, function and therapeutic potential.Endocrine oncology (Bristol, England) · 2025Review
- Review
- N-terminal domain of androgen receptor is a major therapeutic barrier and potential pharmacological target for treating castration resistant prostate cancer: a comprehensive review.Frontiers in pharmacology · 2024Review
- Article
- A New Tool to Study the Binding Behavior of Intrinsically Disordered Proteins.International journal of molecular sciences · 2023Article
- A tile model of circuit topology for self-entangled biopolymers.Scientific reports · 2023Article
- Circuit Topology Approach for the Comparative Analysis of Intrinsically Disordered Proteins.Journal of chemical information and modeling · 2023Article
- A hotspot for posttranslational modifications on the androgen receptor dimer interface drives pathology and anti-androgen resistance.Science advances · 2023Article
- Addressing the Reciprocal Crosstalk between the AR and the PI3K/AKT/mTOR Signaling Pathways for Prostate Cancer Treatment.International journal of molecular sciences · 2023Review
- Topological dynamics of an intrinsically disordered N-terminal domain of the human androgen receptor.Protein science : a publication of the Protein Society · 2022Article
- The role of ubiquitination in spinal and bulbar muscular atrophy.Frontiers in molecular neuroscience · 2022Review
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Authors and funding
9 authors at 3 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Human androgen receptor contains a large N-terminal domain (AR-NTD) that is highly dynamic and this poses a major challenge for experimental and computational analysis to decipher its conformation. Misfolding of the AR-NTD is implicated in prostate cancer and Kennedy's disease, yet our knowledge of its structure is limited to primary sequence information of the chain and a few functionally important secondary structure motifs. Here, we employed an innovative combination of molecular dynamics simulations and circuit topology (CT) analysis to identify the tertiary structure of AR-NTD. We found that the AR-NTD adopts highly dynamic loopy conformations with two identifiable regions with distinct topological make-up and dynamics. This consists of a N-terminal region (NR, residues 1-224) and a C-terminal region (CR, residues 225-538), which carries a dense core. Topological mapping of the dynamics reveals a traceable time-scale dependent topological evolution. NR adopts different positioning with respect to the CR and forms a cleft that can partly enclose the hormone-bound ligand-binding domain (LBD) of the androgen receptor. Furthermore, our data suggest a model in which dynamic NR and CR compete for binding to the DNA-binding domain of the receptor, thereby regulating the accessibility of its DNA-binding site. Our approach allowed for the identification of a previously unknown regulatory binding site within the CR core, revealing the structural mechanisms of action of AR inhibitor EPI-001, and paving the way for other drug discovery applications.
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