Comparison of crystal structures of human androgen receptor ligand-binding domain complexed with various agonists reveals molecular determinants responsible for binding affinity

Oncology and Molecular Endocrinology Research Center, Laval University Medical Center (CHUL) and Laval University, Québec, QC G1V 4G2, Canada.
Protein Science (Impact Factor: 2.85). 06/2006; 15(5):987-99. DOI: 10.1110/ps.051905906
Source: PubMed


Androgens exert their effects by binding to the highly specific androgen receptor (AR). In addition to natural potent androgens, AR binds a variety of synthetic agonist or antagonist molecules with different affinities. To identify molecular determinants responsible for this selectivity, we have determined the crystal structure of the human androgen receptor ligand-binding domain (hARLBD) in complex with two natural androgens, testosterone (Testo) and dihydrotestosterone (DHT), and with an androgenic steroid used in sport doping, tetrahydrogestrinone (THG), at 1.64, 1.90, and 1.75 A resolution, respectively. Comparison of these structures first highlights the flexibility of several residues buried in the ligand-binding pocket that can accommodate a variety of ligand structures. As expected, the ligand structure itself (dimension, presence, and position of unsaturated bonds that influence the geometry of the steroidal nucleus or the electronic properties of the neighboring atoms, etc.) determines the number of interactions it can make with the hARLBD. Indeed, THG--which possesses the highest affinity--establishes more van der Waals contacts with the receptor than the other steroids, whereas the geometry of the atoms forming electrostatic interactions at both extremities of the steroid nucleus seems mainly responsible for the higher affinity measured experimentally for DHT over Testo. Moreover, estimation of the ligand-receptor interaction energy through modeling confirms that even minor modifications in ligand structure have a great impact on the strength of these interactions. Our crystallographic data combined with those obtained by modeling will be helpful in the design of novel molecules with stronger affinity for the AR.

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    • "; (3) LBD (in orange ribbon) and the ligand testosterone bound at the ligand-binding site (PDB ID: 2AM9) [165]; (4) LBD with a small molecule inhibitor bound at the AF-2 site (PDB ID: 2YHD) [35]; and (5) LBD with a small molecule inhibitor bound at the BF-3 site (PDB ID: 4HLW) [37]. No structural model of the N-terminal regions is available. "
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    ABSTRACT: Nuclear receptors (NRs), a family of 48 transcriptional factors, have been studied intensively for their roles in cancer development and progression. The presence of distinctive ligand binding sites capable of interacting with small molecules has made NRs attractive targets for developing cancer therapeutics. In particular, a number of drugs have been developed over the years to target human androgen- and estrogen receptors for the treatment of prostate cancer and breast cancer. In contrast, orphan nuclear receptors (ONRs), which in many cases lack known biological functions or ligands, are still largely under investigated. This review is a summary on ONRs that have been implicated in prostate and breast cancers, specifically retinoic acid-receptor-related orphan receptors (RORs), liver X receptors (LXRs), chicken ovalbumin upstream promoter transcription factors (COUP-TFs), estrogen related receptors (ERRs), nerve growth factor 1B-like receptors, and "dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1" (DAX1). Discovery and development of small molecules that can bind at various functional sites on these ONRs will help determine their biological functions. In addition, these molecules have the potential to act as prototypes for future drug development. Ultimately, the therapeutic value of targeting the ONRs may go well beyond prostate and breast cancers.
    Cancer Treatment Reviews 10/2014; 40(10). DOI:10.1016/j.ctrv.2014.10.005 · 7.59 Impact Factor
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    • "Even though there is no crystal or solution structure of the full length AR unlike other NRs [64] [65] [66], both the DBD and LBD domain structures have been solved individually [9] [59] [67]. Unlike the DBD of AR, whereby only one crystal structure has been elucidated, the LBD of AR has been crystallized in its holostructure together with many agonists in its wild type (WT) form [8] [9] [13] and many antagonists with mutated AR [68] [69]. The first crystal structure of AR was solved by Matias et al., in 2000 and it proved that AR has a similar three dimensional structure with other NRs previously elucidated [8] [70] [71] [72]. "

    Androgen Receptors: Structural Biology, Genetics and Molecular Defects., 2014 edited by Silvia Socorro, 01/2014: chapter Structural and Functional Analysis of the Androgen Receptor in Disease: pages 53-81; Nova., ISBN: 978-1-62948-693-2
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    • "As noted above, the primary changes in prostate disorders are mediated by the conversion of the principle androgen , testosterone, to its more potent metabolite, 5α- DHT [1] [2] [7] [8] [9]. Notably, testosterone's binding affinity for androgen receptors (AR) is approximately 11 nM while 5α-DHT's binding affinity for AR is approximately 1 to 3.5 nM [10] [11]. This suggests that 5α-DHT's androgen hormone action is approximately 5-times greater than testosterone and explains, in part, the effects of this potent metabolite in prostate disorders. "

    Open Journal of Endocrine and Metabolic Diseases 01/2014; 04(01):1-12. DOI:10.4236/ojemd.2014.41001
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