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Synergistic Regulation of Coregulator/Nuclear Receptor Interaction by Ligand and DNA
- Source :
- Structure. 25:1506-1518.e4
- Publication Year :
- 2017
- Publisher :
- Elsevier BV, 2017.
-
Abstract
- 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 13C-detected nuclear magnetic 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 gamma-retinoid X receptor alpha (PPARγ-RXRα) heterodimer and reveal the binding determinants of the complex. Our data reveal a thermodynamic mechanism by which DNA binding propagates a conformational change in PPARγ-RXRα, stabilizes the receptor ligand binding domain dimer interface, and impacts ligand potency and cooperativity in NR coactivator recruitment.
- Subjects :
- 0301 basic medicine
Cooperativity
Retinoid X receptor
Ligands
Article
Nuclear Receptor Coactivator 2
03 medical and health sciences
Structural Biology
Coactivator
Humans
Carbon-13 Magnetic Resonance Spectroscopy
Molecular Biology
Nuclear receptor co-repressor 1
Binding Sites
Retinoid X Receptor alpha
030102 biochemistry & molecular biology
Chemistry
Deuterium Exchange Measurement
DNA
Ligand (biochemistry)
PPAR gamma
Nuclear receptor coactivator 1
030104 developmental biology
Gene Expression Regulation
Nuclear receptor
Biochemistry
Multiprotein Complexes
Biophysics
Nuclear receptor coactivator 2
Protein Binding
Subjects
Details
- ISSN :
- 09692126
- Volume :
- 25
- Database :
- OpenAIRE
- Journal :
- Structure
- Accession number :
- edsair.doi.dedup.....2a92b0ab93fe1336ef54951f6c0bea8c
- Full Text :
- https://doi.org/10.1016/j.str.2017.07.019