Chemistry and conformation of vitamin D molecules

Okamura, William H.; Midland, M. Mark; Hammond, Marion W.; Rahman, Noorsaadah Abd.; Dormanen, Murray C.; Nemere, Ilka; Norman, Anthony W.

doi:10.1016/0960-0760(95)00107-b

Cited by 80 publications

(51 citation statements)

References 23 publications

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“…When these contact sites are occupied, the ligand will be stabilized within the ligand binding pocket by several minor interactions that depend on the structure and flexibility of the ligand side chain and thus may differ between different ligands. Calcitriol and many of its analogs are very flexible compared with other steroid/nuclear hormones because of the open B-ring structure (Bouillon et al, 1995;Okamura et al, 1995). Therefore, they can change their conformation to fit into the ligand binding pocket and to reach the potential ligand contact sites.…”

Section: Discussionmentioning

confidence: 99%

Structurally and Functionally Important Amino Acids of the Agonistic Conformation of the Human Vitamin D Receptor

et al. 2002

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The crystal structures of the ligand binding domain of human vitamin D receptor (VDR) complexed with its natural ligand or the superagonists MC1288 or KH1060 have recently been reported. The crystallized ligand binding domain (LBD) of VDR, however, differs from the full-length VDR with respect to deletion of 50 amino acids between its helices 2 and 3. In this study, we investigated structurally and functionally important amino acid interactions within the ligand binding pocket of the fulllength VDR in the presence of several synthetic vitamin D 3 analogs. We used site-directed mutagenesis scanning combined with limited proteolytic digestion, electrophoretic mobility shift assay, and reporter gene assay and correlated the findings with the crystal structures of truncated VDR LBD. Our results suggest that structurally different agonists have distinct ligandreceptor interactions and that the amino acid residues H229, D232, E269, F279, and Y295 are critical for the agonistic conformation of the VDR. Our biological data, which were obtained with the full-length VDR, fit well with the crystal structure of the truncated VDR LBD and suggest that removal of the insertion domain between helices 2 and 3 of the receptor does not markedly influence the functionality of the VDR.The biologically active form of vitamin D 3 , 1␣,25-dihydroxyvitamin D 3 (calcitriol), regulates several important physiological and biochemical functions in mammals, such as calcium and phosphorus homeostasis as well as cellular growth, differentiation, and apoptosis (DeLuca et al., 1990;Walters, 1992). Binding of calcitriol to its receptor (VDR) induces a conformational change in the receptor and promotes formation of a heterodimer with retinoid X receptor (RXR) as well as binding of other transcriptional cofactors to the receptor. The VDR-RXR heterodimer attaches to a specific segment of DNA, the vitamin D response element (VDRE), which is located in the promoter regions of calcitriol target genes (Carlberg, 1995(Carlberg, , 1996Toell et al., 2000).The VDR belongs to the nuclear receptor superfamily. Many members of this superfamily have conserved amino acid sequences in the C terminus of the receptor (Wurtz et al., 1996;Haussler et al., 1998). VDR, however, makes an exception in that it has a long, unordered loop structure between helices 2 and 3. The LBDs of several nuclear receptors have already been successfully crystallized (Bourguet et al., 1995;Renaud et al., 1995;Wagner et al., 1995;Brzozowski et al., 1997;Williams and Sigler, 1998;Pike et al., 1999;Gampe et al., 2000;Egea et al., 2000;Clayton et al., 2001;Watkins et al., 2001), and a clear homology can be observed in their three-dimensional structures because they share a common helical sandwich structure with three layers of ␣-helices surrounding the hydrophobic ligand binding pocket. When the crystal structure of truncated VDR LBD was solved by Rochel et al. (2000), it could be observed that VDR does not make an exception to the structural principles of related receptors. However,...

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Section: Discussionmentioning

confidence: 99%

Structurally and Functionally Important Amino Acids of the Agonistic Conformation of the Human Vitamin D Receptor

et al. 2002

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“…Similar to the structurally flexible ligand 1a,25 (OH) 2 D 3 (Okamura et al, 1995), curcumin can associate with both VDR domains (Menegaz et al, 2011). By using radiolabeling, it was demonstrated that curcumin competes with 0.4 nM 1a,25(OH) 2 D 3 for VDR binding with a K i of 2.9 mM (Bartik et al, 2010) when assuming a K d of 10 210 M for the 1a,25(OH) 2 D 3 -VDR complex (Bouillon et al, 2008).…”

Section: Evasion Of Immune Destruction (H-iv)mentioning

confidence: 99%

The Molecular Basis for the Pharmacokinetics and Pharmacodynamics of Curcumin and Its Metabolites in Relation to Cancer

Golen²,

et al. 2013

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“…This work reports the synthesis and physicochemical properties of new quaternary alkylammonium conjugates of ergosteryl 3β-bromoacetate (4), cholesteryl 3β-bromoacetate (5) and dihydrocholesteryl 3β-bromoacetate (6) with N,N-dimethyl-N-octylamine (7,11,15), N,N-dimethyl-N-decylamine (8,12,16), N,N-dimethyl-N-dodecylamine (9,13,17), N,N-dimethyl-N-tetradecylamine (10, 14, 18) in acetonitrile. The potential pharmacological activities of the synthesized compounds have been studied using a computer-aided drug discovery approach with the in silico Prediction of Activity Spectra for Substances (PASSs) program.…”

Section: Introductionmentioning

confidence: 99%

“…They are also the main sex hormones in mammals (e.g., testosterone and estrogens) and plants (e.g., brassinosteroids). They also regulate metabolism (e.g., glycocholic and taurocholic acid or vitamin D) and are important cardioactive glycosides (e.g., digoxin, gitoxin and scillaren A) [3][4][5][6]. Exceptionally interesting group of steroids are the sterols, e.g., cholesterol, cholestanol, ergosterol and stigmasterol [7][8][9].…”

Section: Introductionmentioning

confidence: 99%

Synthesis, Spectroscopic and Semiempirical Studies of New Quaternary Alkylammonium Conjugates of Sterols

et al. 2013

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New quaternary alkylammonium conjugates of steroids were obtained by two step reaction of sterols (ergosterol, cholesterol, dihydrocholesterol) with bromoacetic acid bromide, followed by bimolecular nucleophilic substitution with a long chain tertiary alkylamine. The structures of products were confirmed by spectral ( 1 H-NMR, 13 C-NMR, and FT-IR) analysis, mass spectrometry and PM5 semiempirical methods. The pharmacotherapeutic potential of synthesized compounds has been estimated on the basis of Prediction of Activity Spectra for Substances (PASS).

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Chemistry and conformation of vitamin D molecules

Cited by 80 publications

References 23 publications

Structurally and Functionally Important Amino Acids of the Agonistic Conformation of the Human Vitamin D Receptor

Structurally and Functionally Important Amino Acids of the Agonistic Conformation of the Human Vitamin D Receptor

The Molecular Basis for the Pharmacokinetics and Pharmacodynamics of Curcumin and Its Metabolites in Relation to Cancer

Synthesis, Spectroscopic and Semiempirical Studies of New Quaternary Alkylammonium Conjugates of Sterols

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