2002
DOI: 10.1021/jm011072j
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Structural Basis for the Glucocorticoid Response in a Mutant Human Androgen Receptor (ARccr) Derived from an Androgen-Independent Prostate Cancer

Abstract: The crystal structure of a mutant androgen receptor (AR) ligand-binding domain (LBD) in complex with the agonist 9alpha-fluorocortisol has been determined at 1.95 A resolution. This mutant AR contains two mutations (L701H and T877A) and was previously reported as a high-affinity cortisol/cortisone responsive AR (AR(ccr)) isolated from the androgen-independent human prostate cancer cell lines MDA PCa 2a and 2b (Zhao et al. Nature Med. 2000, 6, 703-6). The three-dimensional structure of the AR(ccr) LBD complexed… Show more

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Cited by 78 publications
(61 citation statements)
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“…Purification of AR LBD bound to agonist ligands is well documented and involves removal of contamination chaperones, dnak and groEL, through cation exchange chromatography (21). The AR LBD is not retained by cation exchange chromatography in the presence of antagonist compounds and co-elutes with groEL after anion exchange chromatography, suggesting that antagonist-bound AR LBD is tightly associated with groEL, possibly as a result of partial receptor unfolding (25)(26)(27)(28).…”
Section: Resultsmentioning
confidence: 99%
“…Purification of AR LBD bound to agonist ligands is well documented and involves removal of contamination chaperones, dnak and groEL, through cation exchange chromatography (21). The AR LBD is not retained by cation exchange chromatography in the presence of antagonist compounds and co-elutes with groEL after anion exchange chromatography, suggesting that antagonist-bound AR LBD is tightly associated with groEL, possibly as a result of partial receptor unfolding (25)(26)(27)(28).…”
Section: Resultsmentioning
confidence: 99%
“…To further validate the selected models, ligand poses, after redocking of each of the 24 known AR antagonists, were manually inspected, with special attention to interactions of the ligands with receptor amino acids previously shown to be important for high-affinity binding by the AR LBD (22,(26)(27)(28)(29)(30). In particular, the formation of a hydrogen bond between ligands and R752 is speculated to be essential for high-affinity binding.…”
Section: Resultsmentioning
confidence: 99%
“…Here, we describe and validate a computational method to identify secondary antiandrogen activity of known drugs. By capitalizing on several critical contributions to the understanding of the AR structure and function (20)(21)(22)(23)(24), multiple models for antagonist-bound conformations of the AR were developed, and suitable models for ligand screening were selected based on docking scores for known antagonists. These models were subsequently screened against marketed drugs to identify compounds likely to have secondary antiandrogen activity.…”
mentioning
confidence: 99%
“…Human AR ccr ligand-binding domain was expressed in Escherichia coli and purified according to the procedure of Matias et al (29). Protein concentration was determined using the Bradford protein assay, and aliquots were stored until use at À80jC in 50 mmol/L Tris (pH 7.5) containing 0.8 mol/L NaCl, 10% glycerol, and 1 mmol/L DTT.…”
Section: Subcellular Distribution Of Lycopenementioning
confidence: 99%