Ligand-mediated conformational changes of the VDR are required for gene transactivation

The Journal of Steroid Biochemistry and Molecular Biology
Carsten Carlberg

Abstract

The central element of the molecular switch of nuclear 1alpha,25-dihydroxyvitamin D(3) (1alpha,25(OH)(2)D(3)) signaling is the ligand-binding domain (LBD) of the Vitamin D receptor (VDR), which can be stabilized by 1alpha,25(OH)(2)D(3) or its analogues in to agonistic, antagonistic or inverse agonistic conformations. The positioning of helix 12 of the LBD is of most critical importance for these conformations, because it determines the distance between the charge clamp amino acids K246 and E420 that are essential for VDR-coactivator (CoA) interaction. Most VDR ligands have been identified as agonists and only a few (e.g., ZK168281 and TEI-9647) as pure or partial antagonists. Antagonists induce corepressor (CoR) dissociation from the VDR but prevent completely or partially CoA interaction and thus transactivation. Gemini is a 1alpha,25(OH)(2)D(3) analogue with two identical side chains that despite its significantly increased volume binds to the VDR and acts under most conditions as an agonist. Interestingly, supramolar CoR concentrations shift Gemini from an agonist to an inverse agonist, which actively recruits CoR to the VDR and thus mediates repression of 1alpha,25(OH)(2)D(3) target genes. Gemini is the first described (con...Continue Reading

References

Apr 1, 1995·Endocrine Reviews·R BouillonA W Norman
Feb 18, 1993·Nature·C CarlbergW Hunziker
Oct 1, 1996·Proceedings of the National Academy of Sciences of the United States of America·G C van den BemdJ P van Leeuwen
Jun 26, 1998·Current Opinion in Cell Biology·D Moras, H Gronemeyer
Jul 23, 1998·Critical Reviews in Eukaryotic Gene Expression·C Carlberg, P Polly
Feb 7, 2001·Trends in Endocrinology and Metabolism : TEM·D P McDonnell
Feb 3, 2000·Proceedings of the National Academy of Sciences of the United States of America·M SchapiraR Abagyan
Mar 14, 2000·Gene·C Leo, J D Chen
Jul 6, 2000·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·P PollyC Carlberg
Jan 4, 2001·Trends in Endocrinology and Metabolism : TEM·I Tzameli, D D Moore
May 10, 2001·Proceedings of the National Academy of Sciences of the United States of America·G Tocchini-ValentiniD Moras
May 12, 2001·The Journal of Investigative Dermatology·Y BuryC Carlberg
Dec 1, 2001·Science·A ChawlaD J Mangelsdorf
Jan 10, 2002·Journal of Molecular Biology·Sami VäisänenCarsten Carlberg
May 1, 2002·The EMBO Journal·Paul L Shaffer, Daniel T Gewirth

❮ Previous
Next ❯

Citations

Apr 3, 2012·Biological & Pharmaceutical Bulletin·Masayuki ChumaMakoto Makishima
Nov 26, 2015·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Lin-Yan WanJiang-Feng Wu
May 27, 2008·The Journal of Steroid Biochemistry and Molecular Biology·Seiichi IshizukaG David Roodman
Jul 28, 2006·Chembiochem : a European Journal of Chemical Biology·Nozomi Saito, Atsushi Kittaka
Apr 6, 2012·Molecular and Cellular Endocrinology·Martin WagnerKamil Onder
Feb 3, 2007·Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan·Aya Tanatani
Aug 2, 2007·Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan·Nozomi Saito
Jun 14, 2005·American Journal of Physiology. Renal Physiology·Adriana S DussoEduardo Slatopolsky
Apr 13, 2006·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Claire M BanwellMoray J Campbell

❮ 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.