Structural Insights of Transcriptionally Active, Full-Length Androgen Receptor Coactivator Complexes

Steroid receptors activate gene transcription by recruiting coactivators to initiate transcription of their target genes. For most nuclear receptors, the ligand-dependent activation function domain-2(AF-2) is a primary contributor to the NR transcriptional activity. In contrast to other steroid receptors such as ERα, the activation function of androgen receptor (AR) is largely dependent on its ligand-independent AF-1 located in its N-terminal domain (NTD). It remains unclear why AR utilizes a different AF domain from other receptors despite that NRs share similar domain organizations. Here we present cryoEM structures of DNA-bound full-length AR and its complex structure with key coactivators, SRC-3 and p300. AR dimerization follows a unique head-to-head and tail-to-tail manner. Unlike ERα, AR binds a single SRC-3 and p300. The AR NTD is the primary site for both coactivator recruitment. The structures provide a basis for understanding the assembly of the AR:coactivator complex and its domain contributions for transcriptional regulation.