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 nuclear receptor (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 cryoelectron microscopy (cryo-EM) 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 directly contacts a single SRC-3 and p300. The AR NTD is the primary site for coactivator recruitment. The structures provide a basis for understanding assembly of the AR:coactivator complex and its domain contributions for coactivator assembly and transcriptional regulation. [Display omitted] •Full-length AR follows a unique head-to-head and tail-to-tail dimerization•AR LBD and DBD and NTD all form the dimerization interface•AR interacts with one SRC-3 and one p300•AR N-terminal domain plays a major role in recruiting SRC-3 and p300 Androgen receptor forms a large complex with different coactivators to regulate transcription. Yu et al. demonstrate the first structures of DNA-bound full-length androgen receptor and its assembled complex with coactivators using cryo-EM.