5ZWH

Covalent bond formation between histidine of Vitamin D receptor (VDR) and a full agonist having an ene-ynone group via conjugate addition reaction

5ZWH の概要

• エントリーDOI: 10.2210/pdb5zwh/pdb
• 分子名称: Vitamin D3 receptor, 13-meric peptide from DRIP205 NR2 BOX peptide, (2S)-2-[(1R,3aS,4E,7aR)-7a-methyl-4-[2-[(3R,5R)-4-methylidene-3,5-bis(oxidanyl)cyclohexylidene]ethylidene]-2,3,3a,5,6,7-hexahydro-1H-inden-1-yl]oct-4,6-diene-3-one, ... (5 entities in total)
• 機能のキーワード: hormone covalent modifier transcription factor vitamind3 enone michael addition electrophile, hormone
• 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: 32985.10

構造登録者

Yoshizawa, M.,Itoh, T.,Anami, Y.,Kato, A.,Yoshimoto, N.,Yamamoto, K. (登録日: 2018-05-15, 公開日: 2018-07-18, 最終更新日: 2024-10-23)

主引用文献

Yoshizawa, M.,Itoh, T.,Hori, T.,Kato, A.,Anami, Y.,Yoshimoto, N.,Yamamoto, K.
Identification of the Histidine Residue in Vitamin D Receptor That Covalently Binds to Electrophilic Ligands
J. Med. Chem., 61:6339-6349, 2018

PubMed Abstract: We designed and synthesized vitamin D analogues with an electrophile as covalent modifiers for the vitamin D receptor (VDR). Novel vitamin D analogues 1-4 have an electrophilic enone group at the side chain for conjugate addition to His301 or His393 in the VDR. All compounds showed specific VDR-binding potency and agonistic activity. Covalent bond formations of 1-4 with the ligand-binding domain (LBD) of VDR were evaluated by electrospray ionization mass spectrometry. All compounds were shown to covalently bind to the VDR-LBD, and the abundance of VDR-LBD corresponding conjugate adducts of 1-4 increased with incubation time. Enone compounds 1 and 2 showed higher reactivity than the ene-ynone 3 and dienone 4 compounds. Furthermore, we successfully obtained cocrystals of VDR-LBD with analogues 1-4. X-ray crystallographic analysis showed a covalent bond with His301 in VDR-LBD. We successfully synthesized vitamin D analogues that form a covalent bond with VDR-LBD.

PubMed: 29936834
DOI: 10.1021/acs.jmedchem.8b00774

実験手法

X-RAY DIFFRACTION (2.38 Å)