4G1Z

Structural basis for the accommodation of bis- and tris-aromatic derivatives in Vitamin D Nuclear Receptor

4G1Z の概要

• エントリーDOI: 10.2210/pdb4g1z/pdb
• 関連するPDBエントリー: 4G1D 4G1Y 4G20 4G21 4G2H 4G2I
• 分子名称: Vitamin D3 receptor A, Nuclear receptor coactivator 1, 3-(5'-{[3,4-bis(hydroxymethyl)benzyl]oxy}-2'-ethyl-2-propylbiphenyl-4-yl)pentan-3-ol, ... (4 entities in total)
• 機能のキーワード: vdr, nuclear receptor, transcription regulation, alpha helical sandwich, ligand, dna, phosphorylation, nucleus, transcription-transcription inhibitor complex, transcription/transcription inhibitor
• 由来する生物種: Danio rerio (leopard danio,zebra danio,zebra fish); 詳細
• 細胞内の位置: Nucleus: Q9PTN2; Nucleus (By similarity): Q15788
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 36169.26

構造登録者

Ciesielski, F.,Sato, Y.,Moras, D.,Rochel, N. (登録日: 2012-07-11, 公開日: 2012-09-26, 最終更新日: 2024-02-28)

主引用文献

Ciesielski, F.,Sato, Y.,Chebaro, Y.,Moras, D.,Dejaegere, A.,Rochel, N.
Structural basis for the accommodation of bis- and tris-aromatic derivatives in vitamin d nuclear receptor.
J.Med.Chem., 55:8440-8449, 2012

PubMed Abstract: Actual use of the active form of vitamin D (calcitriol or 1α,25-dihydroxyvitamin D(3)) to treat hyperproliferative disorders is hampered by calcemic effects, hence the continuous development of chemically modified analogues with dissociated profiles. Structurally distinct nonsecosteroidal analogues have been developed to mimic calcitriol activity profiles with low calcium serum levels. Here, we report the crystallographic study of vitamin D nuclear receptor (VDR) ligand binding domain in complexes with six nonsecosteroidal analogues harboring two or three phenyl rings. These compounds induce a stimulated transcription in the nanomolar range, similar to calcitriol. Examination of the protein-ligand interactions reveals the mode of binding of these nonsecosteroidal compounds and highlights the role of the various chemical modifications of the ligands to VDR binding and activity, notably (de)solvation effects. The structures with the tris-aromatic ligands exhibit a rearrangement of a novel region of the VDR ligand binding pocket, helix H6.

PubMed: 22957834
DOI: 10.1021/jm300858s

実験手法

X-RAY DIFFRACTION (2.5 Å)