He B, Gampe Jr RT, Kole AJ, Hnat AT, Stanley TB, An G et al.. Structural basis for androgen receptor interdomain and coactivator interactions suggests a transition in nuclear receptor activation function dominance. Mol Cell 16: 425-438

Laboratories for Reproductive Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Molecular Cell (Impact Factor: 14.02). 12/2004; 16(3):425-38. DOI: 10.1016/j.molcel.2004.09.036
Source: PubMed


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 NH(2)-terminal transactivation domain in the steroid receptor subfamily.

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    • " He et al. (2004). The Surflex-Dock program interfaced with SYBYL 7.3 was adopted to dock the compounds to the ligand binding domain (LBD) of human AR. "
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    • "ligand binding, the AR undergoes several conformational changes including the interdomain interaction between the 23FQNLF27 motif near the amino terminus and the activation function-2 (AF2) domain near the ligand-bound carboxyl terminus (N/C interaction) [42] [43]. This N/C interaction is critical for toxicity through stabilizing the AR and enhancing hormone binding [44] [45]. Selective androgen receptor modulators such as RTI-016 and RTI- 051b prevent the N/C interaction and ameliorated AR aggregation and toxicity while retaining AR transcriptional function, highlighting a novel therapeutic strategy for SBMA (Figure 1) [45]. "
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    • "Such a favoured response reflects a greater dependence of the AR-Pro723S mutant on FKBP52 for normal activity. Pro723 lies within the signature sequence conserved among all steroid receptors (Brelivet et al., 2004), close to a region directly involved in ligand binding and is situated in a solvent exposed loop between helices 3 and 4, which combine together with the mobile helix 12 to form the AF2 coactivator binding pocket (He et al., 2004; Matias et al., 2000b). For AR, AF2 initially has a preferred interaction with the AR N-terminal domain, resulting in an intramolecular fold that precedes receptor dimerization and appears critical for AR function (He et al., 2001; He et al., 2004; Schaufele et al., 2005). "

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