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

Laval University, Quebec City, Quebec, 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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    • "All small molecules currently used as AR-directed therapies for all stages of prostate cancer were developed to target the structured LBD of AR. In fact,Figure 2B represents the crystal structure of the AR LBD in its complex with the tetrahydrogestrinone (THG) bound to the androgenbinding site (Pereira de Tran et al. 2006). It was pointed out that one of the mechanisms underlying failure of small molecules to have prolonged effects as AR-directed therapies and the continued AR transactivation activity may be attributed to the expression of constitutively active splice variants of AR that lack LBD (Banuelos et al. 2014). "
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    ABSTRACT: In higher eukaryotes, proteomes are typically larger than corresponding genomes mostly due to alternative spicing (AS) which is affecting more than 86 % of human genes. Tissue specificity of many proteins is often determined by the AS of pre-mRNAs that generates multiple proteins from a single gene. Aberrations in AS are found in numerous human diseases. This article shows that AS expanded the classic “one-gene–one-protein” paradigm to the “one-gene–many-proteins” concept. AS is intimately associated with protein intrinsic disorder. There is a tight connection between the altered AS of some key intrinsically disordered proteins and pathogenesis of neurodegenerative diseases, cardiovascular disease, cancer, and diabetes. The development of drugs for splice variants is a challenging endeavor. AS has tremendous influence on the applicability of several drugs developed to affect functions typically attributed to the ordered parts of disease-related proteins. Although there are several means for the differential targeting of splice variants, new approaches are obviously needed. It is expected that better understanding of the molecular mechanisms underlying modulation of biological activities of numerous spliced variants will be achieved and new drug design approaches for proteins with multiple splice variants will be developed. © 2016 The Genetics Society of Korea and Springer-Science and Media
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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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    • "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]. "
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