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Synergistic Regulation of Coregulator/Nuclear Receptor Interaction by Ligand and DNA

Authors :
Jie Zheng
Ian Mitchelle S. de Vera
Travis S. Hughes
Douglas J. Kojetin
Jinsai Shang
Richard Brust
David Marciano
William J. Gardner
Paola Munoz-Tello
Patrick R. Griffin
Scott J. Novick
Xiangming Kong
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.

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