Zheng Jie, Chang Mi Ra, Stites Ryan E, Wang Yong, Bruning John B, Pascal Bruce D, Novick Scott J, Garcia-Ordonez Ruben D, Stayrook Keith R, Chalmers Michael J, Dodge Jeffrey A, Griffin Patrick R
Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL, 33458, USA.
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, 46225, USA.
Nat Commun. 2017 Oct 13;8(1):923. doi: 10.1038/s41467-017-00978-7.
The vitamin D receptor/retinoid X receptor-α heterodimer (VDRRXRα) regulates bone mineralization via transcriptional control of osteocalcin (BGLAP) gene and is the receptor for 1α,25-dihydroxyvitamin D (1,25D3). However, supra-physiological levels of 1,25D3 activates the calcium-regulating gene TRPV6 leading to hypercalcemia. An approach to attenuate this adverse effect is to develop selective VDR modulators (VDRMs) that differentially activate BGLAP but not TRPV6. Here we present structural insight for the action of a VDRM compared with agonists by employing hydrogen/deuterium exchange. Agonist binding directs crosstalk between co-receptors upon DNA binding, stabilizing the activation function 2 (AF2) surfaces of both receptors driving steroid receptor co-activator-1 (SRC1) interaction. In contrast, AF2 of VDR within VDRM:BGLAP bound heterodimer is more vulnerable for large stabilization upon SRC1 interaction compared with VDRM:TRPV6 bound heterodimer. These results reveal that the combination of ligand structure and DNA sequence tailor the transcriptional activity of VDR toward specific target genes.The vitamin D receptor/retinoid X receptor-α heterodimer (VDRRXRα) regulates bone mineralization. Here the authors employ hydrogen/deuterium exchange (HDX) mass spectrometry to study the conformational dynamics of VDRRXRα and give mechanistic insights into how VDRRXRα controls the transcriptional activity of specific genes.
维生素D受体/视黄酸X受体-α异二聚体（VDRRXRα）通过对骨钙素（BGLAP）基因的转录控制来调节骨矿化，并且是1α,25-二羟基维生素D（1,25D3）的受体。然而，超生理水平的1,25D3会激活钙调节基因TRPV6，导致高钙血症。一种减轻这种不良反应的方法是开发选择性维生素D受体调节剂（VDRM），其能差异性地激活BGLAP但不激活TRPV6。在此，我们通过氢/氘交换展示了与激动剂相比VDRM作用的结构见解。激动剂结合在DNA结合时引导共受体之间的串扰，稳定两个受体的激活功能2（AF2）表面，驱动类固醇受体共激活因子-1（SRC1）相互作用。相比之下，与VDRM:TRPV6结合的异二聚体相比，VDRM:BGLAP结合的异二聚体内VDR的AF2在与SRC1相互作用时更易受到大幅稳定化的影响。这些结果表明，配体结构和DNA序列的组合决定了VDR对特定靶基因的转录活性。维生素D受体/视黄酸X受体-α异二聚体（VDRRXRα）调节骨矿化。本文作者采用氢/氘交换（HDX）质谱法研究VDRRXRα的构象动力学，并对VDRRXRα如何控制特定基因的转录活性给出了机制性见解。
