4YNK

Crystal structure of vitamin D receptor ligand binding domain complexed with a 19-norvitamin D compound

4YNK の概要

• エントリーDOI: 10.2210/pdb4ynk/pdb
• 分子名称: Vitamin D3 receptor,Vitamin D3 receptor, Coactivator peptide drip from cDNA FLJ50196, highly similar to Peroxisome proliferator-activated receptor-binding protein, (1R,3R,7E,17beta)-17-{(5S)-5-hydroxy-5-[(3R,5R,7R)-tricyclo[3.3.1.1~3,7~]dec-1-yl]penta-1,3-diyn-1-yl}-2-methylidene-9,10-secoestra-5,7-diene-1,3-diol, ... (4 entities in total)
• 機能のキーワード: transcription, hormone receptor
• 由来する生物種: Rattus norvegicus (Rat); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 32666.65

構造登録者

Watarai, Y.,Ikura, T.,Ito, N. (登録日: 2015-03-10, 公開日: 2016-01-20, 最終更新日: 2023-11-08)

主引用文献

Watarai, Y.,Ishizawa, M.,Ikura, T.,Zacconi, F.C.,Uno, S.,Ito, N.,Mourino, A.,Tokiwa, H.,Makishima, M.,Yamada, S.
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
J.Med.Chem., 58:9510-9521, 2015

PubMed Abstract: Novel 19-norvitamin D analogues (ADYW1-4, 5a-d) in which an adamantyl diyne side chain is attached directly to the 17-position of the D ring are designed and stereoselectively synthesized. The adamantane ring of these analogues was expected to interfere with helix 12 (H12, activation function 2) of the vitamin D receptor (VDR) to modulate its activities. The analogue 5b binds to the VDR (7% of the natural hormone) and shows significant partial agonistic activity in transactivation assay. Compound 5b showed considerable selectivity in VDR target genes expressions in vitro, it was taken up by target cells 2-3 times more readily, and its lifetime was three times longer than the natural hormone. The X-ray crystal structure of 5b in complex with VDR reveals that the ligand binds similarly to the natural hormone, but the diyne moiety is slightly bent (angles around the diyne 5° to 8°) with respect to the original diyne vitamin D compound 6 in VDR (<1°) due to steric hindrance with helix 12.

PubMed: 26613420
DOI: 10.1021/acs.jmedchem.5b00792

実験手法

X-RAY DIFFRACTION (2.3 Å)