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

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.