3CS6

Structure-based design of a superagonist ligand for the vitamin D nuclear receptor

3CS6 の概要

• エントリーDOI: 10.2210/pdb3cs6/pdb
• 関連するPDBエントリー: 3CS4
• 分子名称: Vitamin D3 receptor, (1S,3R,5Z,7E,14beta,17alpha,23R)-23-(2-hydroxy-2-methylpropyl)-20,24-epoxy-9,10-secochola-5,7,10-triene-1,3-diol (3 entities in total)
• 機能のキーワード: vdr, agonist, disease mutation, dna-binding, metal-binding, nucleus, phosphoprotein, polymorphism, receptor, transcription, transcription regulation, zinc, zinc-finger, gene regulation
• 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: 30249.99

構造登録者

Hourai, S.,Rodriguez, L.C.,Antony, P.,Reina-San-Martin, B.,Ciesielski, P.,Magnier, B.C.,Schoonjans, K.,Mourino, A.,Rochel, N.,Moras, D. (登録日: 2008-04-09, 公開日: 2008-05-27, 最終更新日: 2024-02-21)

主引用文献

Hourai, S.,Rodrigues, L.C.,Antony, P.,Reina-San-Martin, B.,Ciesielski, F.,Magnier, B.C.,Schoonjans, K.,Mourino, A.,Rochel, N.,Moras, D.
Structure-based design of a superagonist ligand for the vitamin d nuclear receptor.
Chem.Biol., 15:383-392, 2008

PubMed Abstract: Vitamin D nuclear receptor (VDR), a ligand-dependent transcriptional regulator, is an important target for multiple clinical applications, such as osteoporosis and cancer. Since exacerbated increase of calcium serum level is currently associated with VDR ligands action, superagonists with low calcium serum levels have been developed. Based on the crystal structures of human VDR (hVDR) bound to 1alpha,25-dihydroxyvitamin D(3) and superagonists-notably, KH1060-we designed a superagonist ligand. In order to optimize the aliphatic side chain conformation with a subsequent entropy benefit, we incorporated an oxolane ring and generated two stereo diasteromers, AMCR277A and AMCR277B. Only AMCR277A exhibits superagonist activity in vitro, but is as calcemic in vivo as the natural ligand. The crystal structures of the complexes between the ligand binding domain of hVDR and these ligands provide a rational approach to the design of more potent superagonist ligands for potential clinical application.

PubMed: 18420145
DOI: 10.1016/j.chembiol.2008.03.016

実験手法

X-RAY DIFFRACTION (1.8 Å)