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

Mol Cell. 2020 Sep 3;79(5):812-823.e4. doi: 10.1016/j.molcel.2020.06.031. Epub 2020 Jul 14.


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.

Keywords: AR dimerization; N-terminal domain; N/C interaction; SRC-3; androgen receptor; coactivator; complex; cryo-EM; p300; structure.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Cryoelectron Microscopy
  • DNA / chemistry*
  • DNA / metabolism
  • E1A-Associated p300 Protein / chemistry
  • E1A-Associated p300 Protein / metabolism*
  • HEK293 Cells
  • Humans
  • Nuclear Receptor Coactivator 3 / chemistry
  • Nuclear Receptor Coactivator 3 / metabolism*
  • Nucleic Acid Conformation
  • Protein Conformation
  • Receptors, Androgen / chemistry
  • Receptors, Androgen / genetics
  • Receptors, Androgen / metabolism*
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / metabolism


  • Receptors, Androgen
  • Recombinant Proteins
  • DNA
  • E1A-Associated p300 Protein
  • EP300 protein, human
  • NCOA3 protein, human
  • Nuclear Receptor Coactivator 3