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.

类固醇受体通过招募共激活因子来启动其靶基因的转录来激活基因转录。对于大多数核受体，配体依赖性激活功能域 2 (AF-2) 是核受体 (NR) 转录活性的主要贡献者。与其他类固醇受体（如 ERα）相比，雄激素受体 (AR) 的激活功能很大程度上取决于位于其 N 端结构域 (NTD) 的非配体依赖性 AF-1。尽管 NR 共享相似的域组织，但仍不清楚为什么 AR 使用与其他受体不同的 AF 域。在这里，我们展示了 DNA 结合的全长 AR 的低温电子显微镜 (cryo-EM) 结构及其与关键共激活因子 SRC-3 和 p300 的复杂结构。AR 二聚化遵循独特的头对头和尾对尾方式。与 ERα 不同，AR 直接联系单个 SRC-3 和 p300。AR NTD 是辅助激活剂招募的主要场所。这些结构为理解 AR 的组装提供了基础：辅激活剂复合物及其对辅激活剂组装和转录调控的结构域贡献。