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

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 L XX LL motifs of coactivators, the AR ligand binding domain is preferentially engaged in an interdomain interaction with the AR F XX LF motif. Reported here are crystal structures of the ligand-activated AR ligand binding domain with and without bound F XX LF and L XX LL 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 L XX LL motif binding. An activation function transition hypothesis is proposed in which an evolutionary decline in L XX LL motif binding parallels expansion and functional dominance of the NH 2 -terminal transactivation domain in the steroid receptor subfamily.