7bo6

VDR complex with LCA derivativeVDR complex with LCA derivative

Structural highlights

7bo6 is a 2 chain structure with sequence from Danio rerio and Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.86Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

VDRA_DANRE Nuclear hormone receptor. Transcription factor that mediates the action of vitamin D3 by controlling the expression of hormone sensitive genes. Regulates transcription of hormone sensitive genes via its association with the WINAC complex, a chromatin-remodeling complex. Plays a central role in calcium homeostasis.^[1]

Publication Abstract from PubMed

The hypercalcemic effects of the hormone 1alpha,25-dihydroxyvitamin D(3) (calcitriol) and most of known vitamin D metabolites and analogs call for the development of non secosteroidal vitamin D receptor (VDR) ligands as new selective and noncalcemic agonists for treatment of hyperproliferative diseases. We report on the in silico design and stereoselective synthesis of six lithocholic acid derivatives as well as on the calcemic activity of a potent LCA derivative and its crystallographic structure in complex with zVDR LBD. The low calcemic activity of this compound in comparison with the native hormone makes it of potential therapeutic value. Structure-function relationships provide the basis for the development of even more potent and selective lithocholic acid-based VDR ligands.

Lithocholic acid-based design of noncalcemic vitamin D receptor agonists.,Gaikwad S, Gonzalez CM, Vilarino D, Lasanta G, Villaverde C, Mourino A, Verlinden L, Verstuyf A, Peluso-Iltis C, Rochel N, Berkowska K, Marcinkowska E Bioorg Chem. 2021 Jun;111:104878. doi: 10.1016/j.bioorg.2021.104878. Epub 2021 , Mar 30. PMID:33853023^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Ciesielski F, Rochel N, Moras D. Adaptability of the Vitamin D nuclear receptor to the synthetic ligand Gemini: remodelling the LBP with one side chain rotation. J Steroid Biochem Mol Biol. 2007 Mar;103(3-5):235-42. Epub 2007 Jan 10. PMID:17218092 doi:http://dx.doi.org/10.1016/j.jsbmb.2006.12.003
↑ Gaikwad S, González CM, Vilariño D, Lasanta G, Villaverde C, Mouriño A, Verlinden L, Verstuyf A, Peluso-Iltis C, Rochel N, Berkowska K, Marcinkowska E. Lithocholic acid-based design of noncalcemic vitamin D receptor agonists. Bioorg Chem. 2021 Jun;111:104878. PMID:33853023 doi:10.1016/j.bioorg.2021.104878

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OCA

[1] Ciesielski F, Rochel N, Moras D. Adaptability of the Vitamin D nuclear receptor to the synthetic ligand Gemini: remodelling the LBP with one side chain rotation. J Steroid Biochem Mol Biol. 2007 Mar;103(3-5):235-42. Epub 2007 Jan 10. PMID:17218092 doi:http://dx.doi.org/10.1016/j.jsbmb.2006.12.003

[2] Gaikwad S, González CM, Vilariño D, Lasanta G, Villaverde C, Mouriño A, Verlinden L, Verstuyf A, Peluso-Iltis C, Rochel N, Berkowska K, Marcinkowska E. Lithocholic acid-based design of noncalcemic vitamin D receptor agonists. Bioorg Chem. 2021 Jun;111:104878. PMID:33853023 doi:10.1016/j.bioorg.2021.104878

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