7ZFG

VDR complex with aromatic D-ring analog

7ZFG の概要

• エントリーDOI: 10.2210/pdb7zfg/pdb
• 分子名称: Vitamin D3 receptor A, Nuclear receptor coactivator 1, ACETATE ION, ... (5 entities in total)
• 機能のキーワード: complex, agonist, vitamin d receptor, transcription
• 由来する生物種: Danio rerio (zebrafish); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 36394.53

構造登録者

Rochel, N. (登録日: 2022-04-01, 公開日: 2022-11-23, 最終更新日: 2024-01-31)

主引用文献

Seoane, S.,Gogoi, P.,Zarate-Ruiz, A.,Peluso-Iltis, C.,Peters, S.,Guiberteau, T.,Maestro, M.A.,Perez-Fernandez, R.,Rochel, N.,Mourino, A.
Design, Synthesis, Biological Activity, and Structural Analysis of Novel Des-C-Ring and Aromatic-D-Ring Analogues of 1 alpha ,25-Dihydroxyvitamin D 3.
J.Med.Chem., 65:13112-13124, 2022

PubMed Abstract: The toxic calcemic effects of the natural hormone 1α,25-dihydroxyvitamin D (1,25D, 1,25-dihydroxycholecalciferol) in the treatment of hyperproliferative diseases demand the development of highly active and noncalcemic vitamin D analogues. We report the development of two highly active and noncalcemic analogues of 1,25D that lack the C-ring and possess an -phenylene ring that replaces the natural D-ring. The new analogues (, ) are characterized by an additional six-carbon hydroxylated side chain attached either to the aromatic nucleus or to the triene system. Both compounds were synthesized by the Pd-catalyzed tandem cyclization/cross coupling approach starting from alkyne and diphenol . Key steps include a stereoselective Cu-assisted addition of a Grignard reagent to an aromatic alkyne and a Takai olefination of an aromatic aldehyde. The new compounds are noncalcemic and show transcriptional and antiproliferative activities similar to 1,25D. Structural analysis revealed that they induce a large conformational rearrangement of the vitamin D receptor around helix 6.

PubMed: 36166643
DOI: 10.1021/acs.jmedchem.2c00900

実験手法

X-RAY DIFFRACTION (2.62 Å)