Intrinsic disorder in the androgen receptor: identification, characterisation and drugability

The androgen receptor (AR) regulates networks of genes in response to the steroid hormones testosterone and dihydrotestosterone. The receptor protein is made up of both stably folded globular domains, involved in hormone and DNA binding, and regions of intrinsic disorder, including the N-terminal domain (NTD). The AR-NTD has a modular activation function (termed AF1) and is important for gene regulation, participating in multiple protein-protein interactions. Biophysical studies have revealed that AR-NTD/AF1 has limited stable secondary structure and conforms to a 'collapsed disordered' conformation. The AR-NTD/AF1 has the propensity to adopt an α-helical conformation in response to a natural osmolyte or a co-regulatory binding partner. The AR is a key drug target in the management of advanced prostate cancer and recently a small molecule inhibitor was identified that interacts with the NTD/AF1 and impairs protein-protein interactions and recruitment of the receptor to target genes. In this review the role of intrinsic disorder in AR function is discussed along with the potential to develop new drugs that will target the structurally plastic NTD.