Topological dynamics of an intrinsically disordered N-terminal domain of the human androgen receptor

Vahid Sheikhhassani, Barbara Scalvini, Julian Ng, Laurens W H J Heling, Yosri Ayache, Tom M J Evers, Eva Estébanez-Perpiñá, Iain J McEwan, Alireza Mashaghi

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

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.

Original languageEnglish
Article numbere4334
Number of pages17
JournalProtein science : a publication of the Protein Society
Volume31
Issue number6
Early online date26 May 2022
DOIs
Publication statusPublished - Jun 2022

Keywords

  • Androgen Receptor Antagonists/chemistry
  • DNA
  • Humans
  • Male
  • Prostatic Neoplasms/metabolism
  • Protein Domains
  • Receptors, Androgen/chemistry

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