Structural basis for androgen receptor interdomain and coactivator interactions suggests a transition in nuclear receptor activation function dominance

Bin He, Robert T. Gampe, Adam J. Kole, Andrew T. Hnat, Thomas B. Stanley, Gang An, Eugene L. Stewart, Rebecca I. Kalman, John T. Minges, Elizabeth M. Wilson

Research output: Contribution to journalArticle

231 Scopus citations

Abstract

The androgen receptor (AR) is required for male sex development and contributes to prostate cancer cell survival. In contrast to other nuclear receptors that bind the LXXLL motifs of coactivators, the AR ligand binding domain is preferentially engaged in an interdomain interaction with the AR FXXLF motif. Reported here are crystal structures of the ligand-activated AR ligand binding domain with and without bound FXXLF and LXXLL peptides. Key residues that establish motif binding specificity are identified through comparative structure-function and mutagenesis studies. A mechanism in prostate cancer is suggested by a functional AR mutation at a specificity-determining residue that recovers coactivator LXXLL motif binding. An activation function transition hypothesis is proposed in which an evolutionary decline in LXXLL motif binding parallels expansion and functional dominance of the NH2-terminal transactivation domain in the steroid receptor subfamily.

Original languageEnglish (US)
Pages (from-to)425-438
Number of pages14
JournalMolecular Cell
Volume16
Issue number3
DOIs
StatePublished - Nov 5 2004

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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