کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
2186158 1096037 2010 10 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Molecular Switch in the Glucocorticoid Receptor: Active and Passive Antagonist Conformations
موضوعات مرتبط
علوم زیستی و بیوفناوری بیوشیمی، ژنتیک و زیست شناسی مولکولی بیولوژی سلول
پیش نمایش صفحه اول مقاله
Molecular Switch in the Glucocorticoid Receptor: Active and Passive Antagonist Conformations
چکیده انگلیسی

Mifepristone is known to induce mixed passive antagonist, active antagonist, and agonist effects via the glucocorticoid receptor (GR) pathway. Part of the antagonist effects of mifepristone are due to the repression of gene transcription mediated by the nuclear receptor corepressor (NCoR). Here, we report the crystal structure of a ternary complex of the GR ligand binding domain (GR-LBD) with mifepristone and a receptor-interacting motif of NCoR. The structures of three different conformations of the GR-LBD mifepristone complex show in the oxosteroid hormone receptor family how helix 12 modulates LBD corepressor and coactivator binding. Differences in NCoR binding and in helix 12 conformation reveal how the 11β substituent in mifepristone triggers the helix 12 molecular switch to reshape the coactivator site into the corepressor site. Two observed conformations exemplify the active antagonist state of GR with NCoR bound. In another conformation, helix 12 completely blocks the coregulator binding site and explains the passive antagonistic effect of mifepristone on GR.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Journal of Molecular Biology - Volume 395, Issue 3, 22 January 2010, Pages 568–577
نویسندگان
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