2ZL9

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

Summary for 2ZL9

• Entry DOI: 10.2210/pdb2zl9/pdb
• Related: 2ZLA 2ZLC
• Descriptor: Vitamin D3 receptor, Coactivator peptide DRIP, (1R,2R,3R,5Z)-17-{(1S)-1-[(2-ethyl-2-hydroxybutyl)sulfanyl]ethyl}-2-(2-hydroxyethoxy)-9,10-secoestra-5,7,16-triene-1,3-diol, ... (4 entities in total)
• Functional Keywords: protein-ligand complex, dna-binding, metal-binding, nucleus, phosphoprotein, receptor, transcription, transcription regulation, zinc, zinc-finger, hormone
• Biological source: Rattus norvegicus (Rat); More
• Cellular location: Nucleus: P13053
• Total number of polymer chains: 2
• Total formula weight: 32660.66

Authors

Shimizu, M.,Miyamoto, Y.,Nakabayashi, M.,Masuno, H.,Ikura, T.,Ito, N. (deposition date: 2008-04-04, release date: 2008-06-24, Last modification date: 2023-11-01)

Primary citation

Shimizu, M.,Miyamoto, Y.,Takaku, H.,Matsuo, M.,Nakabayashi, M.,Masuno, H.,Udagawa, N.,DeLuca, H.F.,Ikura, T.,Ito, N.
2-Substituted-16-ene-22-thia-1alpha,25-dihydroxy-26,27-dimethyl-19-norvitamin D3 analogs: Synthesis, biological evaluation, and crystal structure
Bioorg.Med.Chem., 16:6949-6964, 2008

PubMed Abstract: 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.

PubMed: 18539034
DOI: 10.1016/j.bmc.2008.05.043

Experimental method

X-RAY DIFFRACTION (1.9 Å)