3A40

Crystal structure of the human VDR ligand binding domain bound to the synthetic agonist compound 2alpha-methyl-AMCR277B(C23R)

3A40 の概要

• エントリーDOI: 10.2210/pdb3a40/pdb
• 関連するPDBエントリー: 1DB1 2HB8 3A3Z 3CS6
• 分子名称: Vitamin D3 receptor, (1S,2S,3R,5Z,7E,14beta,17alpha,23R)-23-(2-hydroxy-2-methylpropyl)-2-methyl-20,24-epoxy-9,10-secochola-5,7,10-triene-1,3-diol, SULFATE ION, ... (4 entities in total)
• 機能のキーワード: transcription, structural genomics, spine2, structural proteomics in europe 2, gene regulation, spine-2
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Nucleus: P11473
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 30456.14

構造登録者

Sato, Y.,Antony, P.,Huet, T.,Sigueiro, R.,Rochel, N.,Moras, D.,Structural Proteomics in Europe 2 (SPINE-2) (登録日: 2009-06-25, 公開日: 2010-02-02, 最終更新日: 2023-11-01)

主引用文献

Antony, P.,Sigueiro, R.,Huet, T.,Sato, Y.,Ramalanjaona, N.,Rodrigues, L.C.,Mourino, A.,Moras, D.,Rochel, N.
Structure-function relationships and crystal structures of the vitamin D receptor bound 2 alpha-methyl-(20S,23S)- and 2 alpha-methyl-(20S,23R)-epoxymethano-1 alpha,25-dihydroxyvitamin D3
J.Med.Chem., 53:1159-1171, 2010

PubMed Abstract: The vitamin D nuclear receptor is a ligand-dependent transcription factor that controls multiple biological responses such as cell proliferation, immune responses, and bone mineralization. Numerous 1 alpha,25(OH)(2)D(3) analogues, which exhibit low calcemic side effects and/or antitumoral properties, have been synthesized. We recently showed that the synthetic analogue (20S,23S)-epoxymethano-1 alpha,25-dihydroxyvitamin D(3) (2a) acts as a 1 alpha,25(OH)(2)D(3) superagonist and exhibits both antiproliferative and prodifferentiating properties in vitro. Using this information and on the basis of the crystal structures of human VDR ligand binding domain (hVDR LBD) bound to 1 alpha,25(OH)(2)D(3), 2 alpha-methyl-1 alpha,25(OH)(2)D(3), or 2a, we designed a novel analogue, 2 alpha-methyl-(20S,23S)-epoxymethano-1 alpha,25-dihydroxyvitamin D(3) (4a), in order to increase its transactivation potency. Here, we solved the crystal structures of the hVDR LBD in complex with the 4a (C23S) and its epimer 4b (C23R) and determined their correlation with specific biological outcomes.

PubMed: 20070104
DOI: 10.1021/jm9014636

実験手法

X-RAY DIFFRACTION (1.45 Å)