Structural perspectives on the androgen receptor, the elusive shape-shifter

Abstract

The androgen receptor (AR) is a type I nuclear receptor and master transcription factor responsible for development and maintenance of male secondary sex characteristics. Aberrant AR activity is associated with numerous diseases, including prostate cancer, androgen insensitivity syndrome, spinal and bulbar muscular atrophy, and androgenic alopecia. Recent studies have shown that AR adopts numerous conformations that can modulate its ability to bind and transcribe its target DNA substrates, a feature that can be hijacked in the context of cancer. Here, we summarize a series of structural observations describing how this elusive shape-shifter binds to multiple partners, including self-interactions, DNA, and steroid and non-steroidal ligands. We present evidence that AR’s pervasive structural plasticity confers an ability to broadly bind and transcribe numerous ligands in the normal and disease state, and explain the structural basis for adaptive resistance mutations to antiandrogen treatment. These evolutionary features are integral to receptor function, and are commonly lost in androgen insensitivity syndrome, or reinforced in cancer.