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: 9.34). 10/2004; 2(9):E274. DOI: 10.1371/journal.pbio.0020274
Source: PubMed


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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    ABSTRACT: Treatment with individual anti-androgens is associated with the development of hot-spot mutations in the androgen receptor (AR). Here, we found that anti-androgens-mt-ARs have similar binary structure to the 5α-dihydrotestosterone-wt-AR. Phage display revealed that these ARs bound to similar peptides, including BUD31, containing an Fxx(F/H/L/W/Y)Y motif cluster with Tyr in the +5 position. Structural analyses of the AR-LBD-BUD31 complex revealed formation of an extra hydrogen bond between the Tyr+5 residue of the peptide and the AR. Functional studies showed that BUD31-related peptides suppressed AR transactivation, interrupted AR N-C interaction, and suppressed AR-mediated cell growth. Combination of peptide screening and X-ray structure analysis may serve as a new strategy for developing anti-ARs that simultaneously suppress both wt and mutated AR function.
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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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    ABSTRACT: The preclinical profiles of two most potent compounds of our recently published cycloalkane[d]isoxazole pharmacophore-based androgen receptor (AR) modulators, FL442 (4-(3a,4,5,6,7,7a-hexahydro-benzo[d]isoxazol-3-yl)-2-trifluoromethylbenzo-nitrile) and its nitro analog FL425 (3-(4-nitro-3-trifluoromethyl-phenyl)-3a,4,5,6,7,7a-hexahydro-benzo[d]-isoxazole), were explored to evaluate their druggability for the treatment of AR dependent prostate cancer. The studies revealed that both compounds are selective to AR over other closely related steroid hormone receptors and that FL442 exhibits equal inhibition efficiency towards the androgen-responsive LNCaP prostate cancer cell line as the most widely used antiandrogen bicalutamide and the more recently discovered enzalutamide. Notably, FL442 maintains antiandrogenic activity with enzalutamide-activated AR mutant F876L. In contrast to bicalutamide, FL442 does not stimulate the VCaP prostate cancer cells which express elevated levels of the AR. Distribution analyses showed that [14CN] FL442 accumulates strongly in the mouse prostate. In spite of its low plasma concentration obtained by intraperitoneal administration, FL442 significantly inhibited LNCaP xenograft tumor growth. These findings provide a preclinical proof for FL442 as a promising AR targeted candidate for a further optimization.
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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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    ABSTRACT: The androgen receptor (AR) has been extensively studied for more than eight decades, due to its regulatory role in the development and maintenance of sexual phenotypes. AR deregulation and association to pathogenesis quickly defined AR as a major target in hormonally responsive diseases such as all stages of prostate cancer (PCa) or androgen insensitivity syndromes (AIS). However, even though there are currently five FDA approved drugs for PCa, AR has been, and still is, a very challenging target due to the disease progression to castrationresistant stages. Several AR-related alterations have been rationalized thanks to structural and functional studies. Due to the hypothesized highly dynamic and flexible nature of AR multi domain structure, many of its physiologically relevant structural states still lack experimental detailed confirmation. However, elucidation of the crystal structures of AR ligand-binding domain (LBD) cocooning the natural ligand dihydrotestosterone as well as the synthetic metribolone bound to its ligand binding pocket (LBP) opened a new window into modulating the mechanism of action of this protein in disease. AR encapsulation of bound ligands reshapes its protein-protein interacting surfaces influencing key macromolecular assemblies. Also may hold true the hypothesis that structural coupling of surface conformations, due to the concrete cellular milieu of coregulators present, may determine differential tissue-specific ligand activities. Additionally, non-ligand binding pocket (non-LBP) druggable sites on the AR LBD and NTD are emerging as alternatives that open rational drug avenues to explore novel anti-androgenic scaffolds. However, a deeper understanding into AR structural plasticity and function in disease still poses many challenges ahead.
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