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7b39

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Allene-Based Design of a Noncalcemic Vitamin D Receptor Agonist

Structural highlights

7b39 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 2.13Å
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

Vitamin D receptor ligands have potential for the treatment of hyperproliferative diseases and disorders related to the immune system. However, hypercalcemic effects limit their therapeutical uses and call for the development of tissue-selective new analogs. We have designed and synthesized the first examples of 1alpha,25-dihydroxyvitamin D(3) analogs bearing an allenic unit attached to the D ring to restrict the side-chain conformational mobility. The triene system was constructed by a Pd(0) -mediated cyclization/Suzuki-Miyaura cross-coupling process in the presence of an allenic side chain. The allenic moiety was built through an orthoester-Claisen rearrangement of a propargylic alcohol. The biological activity and structure of (22S)-1alpha,25-dihydroxy-17,20-dien-24-homo-21-nor-vitamin D(3) bound to binding domain of the vitamin D receptor, provide information concerning side-chain conformational requirements for biological activity.

Design, Synthesis, Evaluation and Structure of Allenic 1alpha,25-Dihydroxyvitamin D(3) Analogs with Locked Mobility at C-17.,Fraga R, Len K, Lutzing R, Laverny G, Loureiro J, Maestro MA, Rochel N, Rodriguez-Borges E, Mourino A Chemistry. 2021 Sep 20;27(53):13384-13389. doi: 10.1002/chem.202101578. Epub 2021 , Aug 11. PMID:34224173^[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
↑ Fraga R, Len K, Lutzing R, Laverny G, Loureiro J, Maestro MA, Rochel N, Rodriguez-Borges E, Mouriño A. Design, Synthesis, Evaluation and Structure of Allenic 1α,25-Dihydroxyvitamin D(3) Analogs with Locked Mobility at C-17. Chemistry. 2021 Sep 20;27(53):13384-13389. PMID:34224173 doi:10.1002/chem.202101578