2OZ7

Crystal structure of the human androgen receptor T877A mutant ligand-binding domain with cyproterone acetate

2OZ7 の概要

• エントリーDOI: 10.2210/pdb2oz7/pdb
• 関連するPDBエントリー: 1i38 1z95 2ax6 2ax7 2axa
• 分子名称: Androgen receptor, CYPROTERONE ACETATE (3 entities in total)
• 機能のキーワード: androgen receptor, anti-androgen, prostate cancer, hormone receptor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Nucleus: P10275
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 29432.99

構造登録者

Bohl, C.E.,Wu, Z.,Miller, D.D.,Bell, C.E.,Dalton, J.T. (登録日: 2007-02-25, 公開日: 2007-03-27, 最終更新日: 2023-08-30)

主引用文献

Bohl, C.E.,Wu, Z.,Miller, D.D.,Bell, C.E.,Dalton, J.T.
Crystal structure of the T877A human androgen receptor ligand-binding domain complexed to cyproterone acetate provides insight for ligand-induced conformational changes and structure-based drug design.
J.Biol.Chem., 282:13648-13655, 2007

PubMed Abstract: Cyproterone acetate (CPA) is a steroidal antiandrogen used clinically in the treatment of prostate cancer. Compared with steroidal agonists for the androgen receptor (AR) (e.g. dihydrotestosterone, R1881), CPA is bulkier in structure and therefore seemingly incompatible with the binding pockets observed in currently available x-ray crystal structures of the AR ligand-binding domain (LBD). We solved the x-ray crystal structure of the human AR LBD bound to CPA at 1.8A in the T877A variant, a mutation known to increase the agonist activity of CPA and therefore facilitate purification and crystal formation of the receptor.drug complex. The structure demonstrates that bulk from the 17alpha-acetate group of CPA induces movement of the Leu-701 side chain, which results in partial unfolding of the C-terminal end of helix 11 and displacement of the loop between helices 11 and 12 in comparison to all other AR LBD crystal structures published to date. This structural alteration leads to an expansion of the AR binding cavity to include an additional pocket bordered by Leu-701, Leu-704, Ser-778, Met-780, Phe-876, and Leu-880. Further, we found that CPA invokes transcriptional activation in the L701A AR at low nanomolar concentrations similar to the T877A mutant. Analogous mutations in the glucocorticoid receptor (GR) and progesterone receptor were constructed, and we found that CPA was also converted into a potent agonist in the M560A GR. Altogether, these data offer information for structure-based drug design, elucidate flexible regions of the AR LBD, and provide insight as to how CPA antagonizes the AR and GR.

PubMed: 17311914
DOI: 10.1074/jbc.M611711200

実験手法

X-RAY DIFFRACTION (1.8 Å)