| Literature DB >> 28890360 |
Ian Mitchelle S de Vera1, Jie Zheng2, Scott Novick2, Jinsai Shang1, Travis S Hughes1, Richard Brust1, Paola Munoz-Tello1, William J Gardner3, David P Marciano2, Xiangming Kong1, Patrick R Griffin2, Douglas J Kojetin4.
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.Entities:
Keywords: NMR spectroscopy; allostery; cooperativity; hydrogen/deuterium exchange (HDX) mass spectrometry; ligand binding; nuclear receptor; peroxisome proliferator-activated receptor; retinoid X receptor; stabilization; transcription
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Year: 2017 PMID： 28890360 PMCID： PMC5653230 DOI： 10.1016/j.str.2017.07.019
Source DB: PubMed Journal: Structure ISSN： 0969-2126 Impact factor: 5.006