Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/118929
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Type: Journal article
Title: HDX reveals the conformational dynamics of DNA sequence specific VDR co-activator interactions
Author: Zheng, J.
Chang, M.
Stites, R.
Wang, Y.
Bruning, J.
Pascal, B.
Novick, S.
Garcia-Ordonez, R.
Stayrook, K.
Chalmers, M.
Dodge, J.
Griffin, P.
Citation: Nature Communications, 2017; 8(1):923-1-923-13
Publisher: Nature Research (part of Springer Nature)
Issue Date: 2017
ISSN: 2041-1723
2041-1723
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Responsibility: 
Jie Zheng, Mi Ra Chang, Ryan E. Stites, Yong Wang, John B. Bruning, Bruce D. Pascal, Scott J. Novick, Ruben D. Garcia-Ordonez, Keith R. Stayrook, Michael J. Chalmers, Jeffrey A. Dodge & Patrick R. Griffin
Abstract: 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 D3 (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.
Keywords: Humans; Hydrogen; Vitamin D; Osteocalcin; Retinoid X Receptors; Receptors, Calcitriol; DNA; Ligands; Deuterium Exchange Measurement; Protein Binding; Dimerization; Mass Spectrometry
Rights: © The Author(s) 2017 This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/ licenses/by/4.0/.
RMID: 0030076834
DOI: 10.1038/s41467-017-00978-7
Appears in Collections:Molecular and Biomedical Science publications

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