Trends in Pharmacological Sciences
Research FocusAndrogen receptor–cofactor interactions as targets for new drug discovery
Section snippets
Cofactor recruitment is an obligate step in nuclear receptor action
The androgen receptor (AR) is a key regulator of processes involved in the growth of prostate cancer cells and thus has emerged as a primary therapeutic target in the management of this disease [1]. The AR is a member of the nuclear receptor superfamily of ligand-regulated transcription factors. As a group, these receptors are involved in diverse activities but share a remarkable structural and functional similarity. In the absence of ligand they exist within target cells in a transcriptionally
The androgen receptor has distinct cofactor preferences
The crystal structure of the AR-LBD in the presence of its cognate agonist was solved several years ago, indicating that, like most nuclear receptors, this particular receptor appeared to contain a coactivator binding pocket 6, 7. However, it was later found that the AR does not abide by the rules established for other nuclear receptors and appears to interact with coactivators in a unique manner. Thus, although the AR-LBD has high sequence homology with the LBDs of other nuclear receptors and
The AR–cofactor interface as a target for drug discovery
All of the known drugs that target the nuclear receptor function by binding to the LBD, thereby inducing the conformational changes intended to either mimic or oppose the effect of the naturally occurring ligand. However, since the discovery of the receptor coactivators and the demonstration that the nuclear receptor–coactivator interface is relatively compact, these protein–protein interfaces are generally considered to be viable drug targets. Indeed, fueled by recent successes in the
Acknowledgements
This work is supported by grants from NCI CA95094 (CYC) and NIDDK DK-065251 (DMD).
References (24)
The structural basis of estrogen receptor/coactivator recognition and the antagonism of this interaction by tamoxifen
Cell
(1998)Structural evidence for ligand specificity in the binding domain of the human androgen receptor. Implications for pathogenic gene mutations
J. Biol. Chem.
(2000)FXXLF and WXXLF sequences mediate the NH2-terminal interaction with the ligand binding domain of the androgen receptor
J. Biol. Chem.
(2000)The use of phage display technique for the isolation of androgen receptor interacting peptides with (F/W)XXL(F/W) and FXXLY new signature motifs
J. Biol. Chem.
(2003)Structural basis for androgen receptor interdomain and coactivator interactions suggests a transition in nuclear receptor activation function dominance
Mol. Cell
(2004)The FXXLF motif mediates androgen receptor-specific interactions with coregulators
J. Biol. Chem.
(2002)Intermolecular NH2-/carboxyl-terminal interactions in androgen receptor dimerization revealed by mutations that cause androgen insensitivity
J. Biol. Chem.
(1998)Molecular determinants of resistance to antiandrogen therapy
Nat. Med.
(2004)Mining the complexities of the estrogen signaling pathways for novel therapeutics
Endocrinology
(2003)A signature motif in transcriptional co-activators mediates binding to nuclear receptors
Nature
(1997)
Ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor-γ
Nature
Crystallographic structures of the ligand-binding domains of the androgen receptor and its T877A mutant complexed with the natural agonist dihydrotestosterone
Proc. Natl. Acad. Sci. U. S. A.
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2019, Molecular and Cellular EndocrinologyCitation Excerpt :Indeed, several groups have shown that peptides that contain (F/W)XXLF motifs bind to the androgen receptor (He et al., 2004; Hur et al., 2004), and some of these motifs are expressed in coregulators that are unique to AR (He et al., 2002). AR can bind larger motifs selectively, and this size-exclusion principle may be used to develop AR-selective CBIs (Chang and McDonnell, 2005). Similarly to SERMs, selective androgen receptor modulators (SARMs) were developed in an effort to exhibit tissue-selectivity.
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2018, Molecular and Cellular EndocrinologyCitation Excerpt :Coregulator Function. More than 200 AR-interacting proteins (both coactivators and corepressors) (Chang and McDonnell, 2005; Heinlein and Chang, 2002), including those with intrinsic functions such as histone acetyl transferase activity (SRCs, CBP) (Smith and O'Malley, 2004), histone deacetylase activity (NCoR, SMRT) (Smith and O'Malley, 2004), and other chromatin modifying functions (SWI/SNF/BRG) (Smith and O'Malley, 2004), have been identified. In addition to several coactivators that are shared by other steroid receptors, a few coactivators such as the ARA family members that exclusively activate the AR have been reported to be expressed in tissues such as prostate (Fujimoto et al., 1999; Kang et al., 1999).
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