Structural basis for the glucocorticoid response in a mutant human androgen receptor (ARccr) derived from an androgen-independent prostate cancer

Pedro M. Matias, Maria Arménia Carrondo, Ricardo Coelho, Monica Thomaz, Xiao Yan Zhao, Anja Wegg, Kerstin Crusius, Ursula Egner, Peter Donner

Research output: Contribution to journalArticle

71 Citations (Scopus)

Abstract

The crystal structure of a mutant androgen receptor (AR) ligand-binding domain (LBD) in complex with the agonist 9α-fluorocortisol has been determined at 1.95 Å resolution. This mutant AR contains two mutations (L701H and T877A) and was previously reported as a high-affinity cortisol/cortisone responsive AR (ARccr) 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 ARccr LBD complexed with 9α-fluorocortisol shows the typical conformation of an agonist-bound nuclear receptor in which helix 12 is precisely positioned as a "lid" for the ligand-binding pocket. Binding of 9α-fluorocortisol to the ARccr involves favorable hydrogen bond patterns on the C17 and C21 substituents of the ligand due to the mutations at 701 and 877 in the ARccr. Our studies provide the first structural explanation for the glucocorticoid activation of ARccr, which is important for the development of new therapeutic treatments for androgen-independent prostate cancer.

Original languageEnglish
Pages (from-to)1439-1446
Number of pages8
JournalJournal Of Medicinal Chemistry
Volume45
Issue number7
DOIs
Publication statusPublished - 28 Mar 2002

Keywords

  • hydrocortisone
  • mutant protein
  • androgen receptor
  • cortisone
  • fludrocortisone
  • glucocorticoid

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