Synthesis, Biological Activities, and X-ray Crystal Structural Analysis of 25-Hydroxy-25(or 26)-adamantyl-17-[20(22),23-diynyl]-21-norvitamin D Compounds

Watarai, Yusuke; Ishizawa, Michiyasu; Ikura, Teikichi; Zacconi, Flavia; Uno, Shigeyuki; Ito, Nobuyasu; Mouriño, Antonio; Tokiwa, Hiroaki; Makishima, Makoto; Yamada, Sachiko

doi:10.1021/acs.jmedchem.5b00792

Cited by 15 publications

(17 citation statements)

References 48 publications

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“…20 hits in CSD), while 63 different vitamin D analogues have been solved as ligands in ca. 115 macromolecular structures. − , Difficulties in crystallization of vitamin D analogues are probably the result of a large conformational space of the compounds and the number of hydrogen bonds that can be formed in crystal lattice. All of vitamin D analogues are insoluble in water, and acetyl acetate solution with dielectric constant of six can reassemble the hydrophobic VDR pocket.…”

Section: Resultsmentioning

confidence: 99%

Effect of Vitamin D Conformation on Interactions and Packing in the Crystal Lattice

Wanat

Malińska

Kutner

et al. 2018

Crystal Growth & Design

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The crystal and molecular structures of a series of structurally related analogues of 1,25-dihydroxyvitamin D2 and of the first analogue with all hydroxyl groups protected were established with single crystal X-ray structural analysis. With the use of the new structural data, we proposed that the A-ring conformation depends on hydrogen bonding of the hydroxyl groups of the A-ring. The A-ring of the 1α-hydroxylated vitamin D analogues exists in the solid state in a preferred chair β-conformation induced by direct hydrogen bonds between the 1-OH and 3-OH hydroxyl groups. In the same A-ring conformation, the vitamin D analogue interacts with the vitamin D receptor. Indirect hydrogen bonds between the A-ring hydroxyl groups, such as the ones through the water molecule, or hydrogen bonds between the A-ring hydroxyl groups and side-chain hydroxyl groups, induce the α-conformation. Theoretical calculations performed in vacuo showed that the β-form has a slightly lower energy than the α-form. Not only the hydroxyl groups but also the exocyclic methylene highly influences intermolecular interactions including the hydrogen bond pattern in the crystal lattices.

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Section: Resultsmentioning

confidence: 99%

Effect of Vitamin D Conformation on Interactions and Packing in the Crystal Lattice

Wanat

Malińska

Kutner

et al. 2018

Crystal Growth & Design

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“…This further emphasizes the impact of vitamin D and VDR for innate and adaptive immunity and suggests that these areas should be further explored for a commercial application …”

Section: Discussionmentioning

confidence: 89%

“…The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jmedchem.9b00208. Table S1 describing all 143 publically available VDR ligand crystal structures with individual hyperlinks to the PDB and PubMed databases and citations of refs − (PDF) …”

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Vitamin D and Its Synthetic Analogs

2019

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For many individuals, in particular during winter, supplementation with the secosteroid vitamin D 3 is essential for the prevention of bone disorders, muscle weakness, autoimmune diseases, and possibly also different types of cancer. Vitamin D 3 acts via its metabolite 1α,25-dihydroxyvitamin D 3 [ 1,25(OH) 2 D 3 ] as potent agonist of the transcription factor vitamin D receptor (VDR). Thus, vitamin D directly affects chromatin structure and gene regulation at thousands of genomic loci, i.e., the epigenome and transcriptome of its target tissues. Modifications of 1,25(OH) 2 D 3 at its side-chain, A-ring, triene system, or C-ring, alone and in combination, as well as nonsteroidal mimics provided numerous potent VDR agonists and some antagonists. The nearly 150 crystal structures of VDR’s ligand-binding domain with various vitamin D compounds allow a detailed molecular understanding of their action. This review discusses the most important vitamin D analogs presented during the past 10 years and molecular insight derived from new structural information on the VDR protein.

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“…Using GST-VDR fusion protein induced by Escherichia coli BL21 DE3, a ligand-binding assay was performed by modification of previously published methods 15 . Briefly, 1 µg of GST fusion proteins was incubated with [ 3 H]1α,25(OH) 2 D 3 (PerkinElmer, USA) for 20 hours at 4 °C.…”

Section: Methodsmentioning

confidence: 99%

Functional analyses of a novel missense and other mutations of the vitamin D receptor in association with alopecia

Tamura

Ishizawa

Isojima

et al. 2017

Sci Rep

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Hereditary 1,25-dihydroxyvitamin D-resistant rickets (HVDRR) is a rare disorder, caused by bialellic mutations of the vitamin D receptor (VDR) gene, sometimes associated with alopecia. The aim of this study is to elucidate the mechanism of functional disruption of a novel mutation, detected in a patient with HVDRR, comparing to other mutations with or without alopecia. The patient was a 2-year-old girl with alopecia, who was clinically diagnosed as HVDRR. Genetic analysis revealed a novel homozygous mutation, S360P, located in ligand binding domain (LBD). The mutation was predicted as not disease causing by Polyphen2 and SIFT. But the transcriptional activity of S360P was disrupted as well as other reported mutations, Q152X (located in the hinge lesion), and R274L, H305Q (located in LBD). Following assays revealed no ligand binding affinity, no interaction with cofactors or RXR and no functioning of nuclear localization signals. Our results provide an additional evidence for the previous findings suggesting that DNA binding by the VDR/RXR heterodimer is essential for the function of the VDR in hair development. In conclusion, we identified a novel missense mutation of VDR causing HVDRR with alopecia. Functional analyses revealed that the single amino acid substitution could disrupt the function of the protein.

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Synthesis, Biological Activities, and X-ray Crystal Structural Analysis of 25-Hydroxy-25(or 26)-adamantyl-17-[20(22),23-diynyl]-21-norvitamin D Compounds

Cited by 15 publications

References 48 publications

Effect of Vitamin D Conformation on Interactions and Packing in the Crystal Lattice

Effect of Vitamin D Conformation on Interactions and Packing in the Crystal Lattice

Vitamin D and Its Synthetic Analogs

Functional analyses of a novel missense and other mutations of the vitamin D receptor in association with alopecia

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