Structure
Volume 25, Issue 10, 3 October 2017, Pages 1506-1518.e4
Journal home page for Structure

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

https://doi.org/10.1016/j.str.2017.07.019Get rights and content
Under an Elsevier user license
open archive

Highlights

  • Structural and biophysical analysis of SRC-2 RID/PPARγ-RXRα interaction

  • Ligand binding to RXRα dominates over PPARγ to enhance interaction with SRC-2 RID

  • DNA binding to PPARγ/RXRα influences SRC-2 RID affinity and vice versa

  • Ligand and DNA cooperatively enhance SRC-2 RID binding to PPARγ/RXRα

Summary

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.

Keywords

allostery
ligand binding
NMR spectroscopy
hydrogen/deuterium exchange (HDX) mass spectrometry
peroxisome proliferator-activated receptor
retinoid X receptor
nuclear receptor
cooperativity
stabilization
transcription

Cited by (0)

4

Present address: Department of Pharmacology & Physiology, Saint Louis University School of Medicine, St. Louis, MO 63104, USA

5

Present address: Department of Biomedical and Pharmaceutical Sciences, University of Montana, Missoula, MT 59812, USA

6

Lead Contact