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HDX reveals the conformational dynamics of DNA sequence specific VDR co-activator interactions

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dc.contributor.authorZheng, J.
dc.contributor.authorChang, M.
dc.contributor.authorStites, R.
dc.contributor.authorWang, Y.
dc.contributor.authorBruning, J.
dc.contributor.authorPascal, B.
dc.contributor.authorNovick, S.
dc.contributor.authorGarcia-Ordonez, R.
dc.contributor.authorStayrook, K.
dc.contributor.authorChalmers, M.
dc.contributor.authorDodge, J.
dc.contributor.authorGriffin, P.
dc.date.issued2017
dc.description.abstractThe 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.
dc.description.statementofresponsibilityJie 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
dc.identifier.citationNature Communications, 2017; 8(1):923-1-923-13
dc.identifier.doi10.1038/s41467-017-00978-7
dc.identifier.issn2041-1723
dc.identifier.issn2041-1723
dc.identifier.orcidBruning, J. [0000-0002-6919-1824]
dc.identifier.urihttp://hdl.handle.net/2440/118929
dc.language.isoen
dc.publisherNature Research (part of Springer Nature)
dc.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/.
dc.source.urihttps://doi.org/10.1038/s41467-017-00978-7
dc.subjectHumans
dc.subjectHydrogen
dc.subjectVitamin D
dc.subjectOsteocalcin
dc.subjectRetinoid X Receptors
dc.subjectReceptors, Calcitriol
dc.subjectDNA
dc.subjectLigands
dc.subjectDeuterium Exchange Measurement
dc.subjectProtein Binding
dc.subjectDimerization
dc.subjectMass Spectrometry
dc.titleHDX reveals the conformational dynamics of DNA sequence specific VDR co-activator interactions
dc.typeJournal article
pubs.publication-statusPublished

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