DNA binding alters coactivator interaction surfaces of the intact VDR–RXR complex
Open Access
- 10 April 2011
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Structural & Molecular Biology
- Vol. 18 (5), 556-563
- https://doi.org/10.1038/nsmb.2046
Abstract
A comprehensive HDX analysis of the vitamin D receptor–retinoid X receptor (VDR-RXR) reveals extensive allosteric communication within the same polypeptide where DNA or ligand can induce alterations in distant domains of the receptors. The work also shows communication between subunits in the heterodimer. The vitamin D receptor (VDR) functions as an obligate heterodimer in complex with the retinoid X receptor (RXR). These nuclear receptors are multidomain proteins, and it is unclear how various domains interact with one another within the nuclear receptor heterodimer. Here, we show that binding of intact heterodimer to DNA alters the receptor dynamics in regions remote from the DNA-binding domains (DBDs), including the coactivator binding surfaces of both co-receptors, and that the sequence of the DNA response element can determine these dynamics. Furthermore, agonist binding to the heterodimer results in changes in the stability of the VDR DBD, indicating that the ligand itself may play a role in DNA recognition. These data suggest a mechanism by which nuclear receptors show promoter specificity and have differential effects on various target genes, providing insight into the function of selective nuclear receptor modulators.Keywords
This publication has 57 references indexed in Scilit:
- Hydrogen/Deuterium Exchange Reveals Distinct Agonist/Partial Agonist Receptor Dynamics within Vitamin D Receptor/Retinoid X Receptor HeterodimerStructure, 2010
- Anti-diabetic drugs inhibit obesity-linked phosphorylation of PPARγ by Cdk5Nature, 2010
- Unique Ligand Binding Patterns between Estrogen Receptor α and β Revealed by Hydrogen−Deuterium ExchangeBiochemistry, 2009
- Conformational disturbance in Abl kinase upon mutation and deregulationProceedings of the National Academy of Sciences of the United States of America, 2009
- HD desktop: An integrated platform for the analysis and visualization of H/D exchange dataJournal of the American Society for Mass Spectrometry, 2008
- Structure of the intact PPAR-γ–RXR-α nuclear receptor complex on DNANature, 2008
- Prediction of the tissue-specificity of selective estrogen receptor modulators by using a single biochemical methodProceedings of the National Academy of Sciences of the United States of America, 2008
- Fly-Casting in Protein−DNA Binding: Frustration between Protein Folding and Electrostatics Facilitates Target RecognitionJournal of the American Chemical Society, 2007
- The retinoid X receptor ligand restores defective signalling by the vitamin D receptorEMBO Reports, 2006
- UCSF Chimera?A visualization system for exploratory research and analysisJournal of Computational Chemistry, 2004