期刊
STRUCTURE
卷 25, 期 10, 页码 1506-+出版社
CELL PRESS
DOI: 10.1016/j.str.2017.07.019
关键词
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资金
- James and Esther King Biomedical Research Program, Florida Department of Health [1KN-09]
- William R. Kenan, Jr. Charitable Trust (TSRI)
- NIH [R01DK101871, R01DK105825, F32DK097890, K99DK103116, F32DK108442]
- American Heart Association (AHA) [12POST12050025, 16POST27780018]
Nuclear receptor (NR) transcription factors bind various coreceptors, small-molecule ligands, DNA response element sequences, and transcriptional coregulator proteins to affect gene transcription. Small-molecule ligands and DNA are known to influence receptor structure, coregulator protein interaction, and function; however, little is known on the mechanism of synergy between ligand and DNA. Using quantitative biochemical, biophysical, and solution structural methods, including 13 C-detected nuclearmagnetic resonance and hydrogen/deuterium exchange (HDX) mass spectrometry, we show that ligand and DNA cooperatively recruit the intrinsically disordered steroid receptor coactivator-2 (SRC-2/TIF2/GRIP1/NCoA-2) receptor interaction domain to peroxisome proliferator-activated receptor gammaretinoid X receptor alpha (PPARg-RXRa) heterodimer and reveal the binding determinants of the complex. Our data reveal a thermodynamic mechanism by which DNA binding propagates a conformational change in PPARg-RXRa, stabilizes the receptor ligand binding domain dimer interface, and impacts ligand potency and cooperativity in NR coactivator recruitment.
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