2zla

2-Substituted-16-ene-22-thia-1alpha,25-dihydroxy-26,27-dimethyl-19-norvitamin D3 analogs: Synthesis, biological evaluation and crystal structure

spinqualitylabelsall models 2zla, resolution 2.00Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 2zla is a 2 chain structure with sequence from Rattus norvegicus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: VDB Related: 2zl9, 2zlc Gene: Vdr, Nr1i1 (Rattus norvegicus) Resources: FirstGlance, OCA, RCSB, PDBsum Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMed Recently, we have found that 16-ene-22-thia-26,27-dimethyl-19-norvitamin D(3) analogs 1a (n=2, 3) are 20 times more active than the natural hormone 1alpha,25-dihydroxyvitamin D(3) in terms of transcriptional activity. To further investigate the effects of the A-ring modification of 1a, b on the biological activity profile, novel 22-thia-19-norvitamin D analogs 2-11 bearing a hydroxyethoxy-, hydroxyethylidene- or methyl group at C-2 in combination with 20S- and 20R-isomers were prepared and tested for their in vitro biological activities. All of the synthesized analogs showed 0.5-140% of the activity of the natural hormone in binding to the vitamin D receptor (VDR). When compared with the transcriptional activity of C-2 or C-20 isomeric pairs of the 22-thia analogs, the 20S-isomers 2-11a were more potent than the 20R-isomers 2, 3, 8-11b, and the 2beta-hydroxyethoxy, 2E-hydroxyethylidene, and 2alpha-methyl-2beta-hydroxy-22-thia isomers showed higher potency than their corresponding counterparts. In particular, 3a exhibited an extremely higher level of potency (210-fold) than the natural hormone. To elucidate the action mode of superagonist 3a at the molecular level, we determined the crystal structures of the rat VDR-ligand-binding domain complexed with 3a or 3b in the presence of peptide containing a nuclear box motif (LxxLL) at 1.9-2.0A resolution. The crystal structures demonstrated that the 1alpha-OH, 3beta-OH, and 25-OH groups of the natural hormone and 3a were anchored by the same amino acid residues in the ligand-binding pocket, and the terminal OH moiety of the substituent at C-2 formed hydrogen bonds with Arg270 and a water molecule to create a tight water molecule network. Moreover, the methyl groups at C-26a and C-27a make additional contact with hydrophobic residues such as Leu223, Ala227, Val230, and Ala299. These hydrophilic and hydrophobic interactions in 3a may underlie the induction of superagonistic activity. 2-Substituted-16-ene-22-thia-1alpha,25-dihydroxy-26,27-dimethyl-19-norvita min D3 analogs: Synthesis, biological evaluation, and crystal structure.,Shimizu M, Miyamoto Y, Takaku H, Matsuo M, Nakabayashi M, Masuno H, Udagawa N, DeLuca HF, Ikura T, Ito N Bioorg Med Chem. 2008 Jul 15;16(14):6949-64. Epub 2008 May 27. PMID:18539034 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Sandbox vdr Vitamin D receptor

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