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

被引：43

作者：

de Vera, Ian Mitchelle S. ^{[1
,2
,4
]}

Zheng, Jie ^{[2
]}

Novick, Scott ^{[2
]}

Shang, Jinsai ^{[1
,2
]}

Hughes, Travis S. ^{[1
,2
,5
]}

Brust, Richard ^{[1
,2
]}

Munoz-Tello, Paola ^{[1
,2
]}

Gardner, William J., Jr. ^{[1
,2
,3
]}

Marciano, David P. ^{[2
]}

Kong, Xiangming ^{[1
,2
]}

Griffin, Patrick R. ^{[2
]}

Kojetin, Douglas J. ^{[1
,2
]}

机构：

[1] Scripps Florida, Scripps Res Inst, Dept Integrat Struct & Computat Biol, Jupiter, FL 33458 USA

[2] Scripps Florida, Scripps Res Inst, Dept Mol Med, Jupiter, FL 33458 USA

[3] Scripps Florida, Scripps Res Inst, TSRI High Sch Student Summer Internship Program, Jupiter, FL 33458 USA

[4] St Louis Univ, Sch Med, Dept Physiol & Pharmacol, St Louis, MO 63104 USA

[5] Univ Montana, Dept Biomed & Pharmaceut Sci, Missoula, MT 59812 USA

来源：

STRUCTURE | 2017年 / 25卷 / 10期

关键词：

RETINOID-X-RECEPTOR; PPAR-GAMMA-RXR; BINDING; EXCHANGE; ALPHA; COMPLEX; ENERGETICS; MECHANISM; DYNAMICS; PEPTIDE;

D O I：

10.1016/j.str.2017.07.019

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：1506 / +

页数：17

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