de Vera Ian Mitchelle S, Zheng Jie, Novick Scott, Shang Jinsai, Hughes Travis S, Brust Richard, Munoz-Tello Paola, Gardner William J, Marciano David P, Kong Xiangming, Griffin Patrick R, Kojetin Douglas J
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, Scripps Florida, Jupiter, FL 33458, USA; Department of Molecular Medicine, The Scripps Research Institute, Scripps Florida, Jupiter, FL 33458, USA.
Department of Molecular Medicine, The Scripps Research Institute, Scripps Florida, Jupiter, FL 33458, USA.
Structure. 2017 Oct 3;25(10):1506-1518.e4. doi: 10.1016/j.str.2017.07.019. Epub 2017 Sep 7.
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 C-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.
核受体（NR）转录因子与各种共受体、小分子配体、DNA反应元件序列和转录共调节蛋白结合，以影响基因转录。已知小分子配体和DNA会影响受体结构、共调节蛋白相互作用和功能；然而，关于配体与DNA协同作用的机制却知之甚少。我们使用定量生化、生物物理和溶液结构方法，包括碳检测核磁共振和氢/氘交换（HDX）质谱，表明配体和DNA协同将内在无序的类固醇受体共激活因子2（SRC-2/TIF2/GRIP1/NCoA-2）受体相互作用域募集到过氧化物酶体增殖物激活受体γ-视黄酸X受体α（PPARγ-RXRα）异二聚体，并揭示了该复合物的结合决定因素。我们的数据揭示了一种热力学机制，通过该机制，DNA结合在PPARγ-RXRα中传播构象变化，稳定受体配体结合域二聚体界面，并影响NR共激活因子募集过程中的配体效力和协同性。
