Article

Recognition and Accommodation at the Androgen Receptor Coactivator Binding Interface

Graduate Group in Biophysics, University of California, San Francisco, California, USA.
PLoS Biology (Impact Factor: 11.77). 10/2004; 2(9):E274. DOI: 10.1371/journal.pbio.0020274
Source: PubMed

ABSTRACT Prostate cancer is a leading killer of men in the industrialized world. Underlying this disease is the aberrant action of the androgen receptor (AR). AR is distinguished from other nuclear receptors in that after hormone binding, it preferentially responds to a specialized set of coactivators bearing aromatic-rich motifs, while responding poorly to coactivators bearing the leucine-rich "NR box" motifs favored by other nuclear receptors. Under normal conditions, interactions with these AR-specific coactivators through aromatic-rich motifs underlie targeted gene transcription. However, during prostate cancer, abnormal association with such coactivators, as well as with coactivators containing canonical leucine-rich motifs, promotes disease progression. To understand the paradox of this unusual selectivity, we have derived a complete set of peptide motifs that interact with AR using phage display. Binding affinities were measured for a selected set of these peptides and their interactions with AR determined by X-ray crystallography. Structures of AR in complex with FxxLF, LxxLL, FxxLW, WxxLF, WxxVW, FxxFF, and FxxYF motifs reveal a changing surface of the AR coactivator binding interface that permits accommodation of both AR-specific aromatic-rich motifs and canonical leucine-rich motifs. Induced fit provides perfect mating of the motifs representing the known family of AR coactivators and suggests a framework for the design of AR coactivator antagonists.

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    • "In contrast, Leuþ4 binds to a shallow, hydrophobic patch in the sidewall of the L-shaped groove and is largely solvent exposed. The other intra-motif and flanking amino acids support the interaction of the peptide with the AR (Hur et al., 2004). Using 5a-dihydrotestosterone (DHT) wild-type AR-DBD- LBD (wt-AR-DBD-LBD) and HF mutant T877A AR-DBD-LBD (HF-T877A-AR-DBD-LBD) as baits, we found that screened peptides were enriched for Tyrþ5. "
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    • "LBD, leading to its interaction with the AR N-terminal transactivation domain (Langley et al., 1995). In addition, the AF2 site conformation is essential for coactivator binding and thereby to the ability of the receptor to activate its target genes (Gao et al., 2005; van de Wijngaart et al., 2012; Hur et al., 2004). The first generation (relatively low affinity) antiandrogens, such as bicalutamide , appear to inhibit the AR activity by inducing partial unfolding of the AR. "
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    • "Upon binding of agonists H12 is repositioned in a " mouse trap " like fashion, completing the LBP [74] [75] [76]. Several AR LBD residues (V713, V716, K717, K720, R726, V730, Q733, M734, I737, Q738, E893, M895, E897 and I899) shape the AF-2 pocket, which belong to H3, H4-H5 and H12 (Figure 1) [10] [77]. The hydrophobic and solvent-exposed AF-2 pocket interacts intimately with the NR boxes present in AR coactivators and the two sequences present in the NTD domain. "
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