Structural analysis of RXR-VDR interactions on DR3 DNA

The Journal of Steroid Biochemistry and Molecular Biology
Paul L Shaffer, Daniel T Gewirth

Abstract

The Vitamin D receptor (VDR) is a ligand-responsive transcription factor that forms homo- or heterodimers on response elements composed of two hexameric half-sites separated by three base pairs of spacer DNA. Binding of 1alpha,25-dihydroxyvitamin D(3) to the full-length VDR causes destabilization of the VDR homodimer and formation of a heterodimeric complex with the 9-cis retinoic acid receptor (RXR). VDR and RXR DNA-binding domains (DBDs) do not mimic this behavior, however: VDR DBD homodimers are formed exclusively, even in the presence of excess RXR DBD. Exploiting the asymmetry of the heterodimer and our knowledge of the homodimeric DBD interface, we have engineered VDR mutants that disfavor the homodimeric complex and allow for the formation of heterodimeric DBD complexes with RXR on DR3 elements. One of these complexes has been crystallized and its structure determined. However, the polarity of the proteins relative to the DNA is non-physiological due to crystal packing between symmetry-related VDR DBD protomers. This reveals a flattened energy landscape that appears to rely on elements outside of the core DBD for response element discrimination in the heterodimer.

References

Mar 1, 1991·Acta Crystallographica. Section A, Foundations of Crystallography·T A JonesM Kjeldgaard
Aug 1, 1981·Proceedings of the National Academy of Sciences of the United States of America·E AbeT Suda
Apr 1, 1995·Endocrine Reviews·R BouillonA W Norman
Jul 1, 1993·Proceedings of the National Academy of Sciences of the United States of America·T L TowersL P Freedman
Jul 1, 1993·Genes & Development·T PerlmannR M Evans
Dec 15, 1995·Cell·D J MangelsdorfR M Evans
Dec 15, 1995·Cell·D J Mangelsdorf, R M Evans
Jul 14, 1998·Molecular Cell·Q ZhaoF Rastinejad
Oct 3, 1998·Acta Crystallographica. Section D, Biological Crystallography·A T BrüngerG L Warren
Mar 4, 2000·The EMBO Journal·F RastinejadS Khorasanizadeh
Jun 19, 2001·Trends in Biochemical Sciences·S Khorasanizadeh, F Rastinejad
Jul 31, 2001·Molecular and Cellular Endocrinology·T MiyamotoK Hashizume
May 1, 2002·The EMBO Journal·Paul L Shaffer, Daniel T Gewirth

❮ Previous
Next ❯

Citations

Jul 23, 2015·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Lin-Yan WanJiang-Feng Wu
May 14, 2008·Clinica Chimica Acta; International Journal of Clinical Chemistry·Indra Ramasamy
Oct 25, 2011·Biochimica Et Biophysica Acta·Marcia I Dawson, Zebin Xia
Mar 6, 2015·Canadian Journal of Physiology and Pharmacology·Carsten Carlberg, Ferdinand Molnár
Jun 18, 2014·Frontiers in Physiology·Ferdinand Molnár
Jun 10, 2017·Transcription·Tatyana Singh, Brian D Adams
Apr 12, 2011·Nature Structural & Molecular Biology·Natacha RochelDino Moras
Jan 16, 2007·Arquivos brasileiros de endocrinologia e metabologia·Cláudia D C Faria, Carlos Alberto Longui
Oct 17, 2017·Nature Communications·Jie ZhengPatrick R Griffin
Oct 6, 2005·The Journal of Biological Chemistry·Rubina YasminNoa Noy
Oct 31, 2017·Endocrinology and Metabolism Clinics of North America·Moray J Campbell, Donald L Trump
Dec 16, 2018·Toxicology and Applied Pharmacology·Andrew J AnnaloraPatrick L Iversen

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.