5ZJA

human D-amino acid oxidase complexed with 5-chlorothiophene-2-carboxylic acid

5ZJA の概要

• エントリーDOI: 10.2210/pdb5zja/pdb
• 関連するPDBエントリー: 5ZJ9
• 分子名称: D-amino-acid oxidase, FLAVIN-ADENINE DINUCLEOTIDE, 5-chloro thiophene-2-carboxylic acid, ... (4 entities in total)
• 機能のキーワード: d-amino acid, flavoenzyme, oxidoreductase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 158592.22

構造登録者

Kato, Y.,Hin, N.,Maita, N.,Thomas, A.G.,Kurosawa, S.,Rojas, C.,Yorita, K.,Slusher, B.S.,Fukui, K.,Tsukamoto, T. (登録日: 2018-03-19, 公開日: 2018-10-10, 最終更新日: 2023-11-22)

主引用文献

Kato, Y.,Hin, N.,Maita, N.,Thomas, A.G.,Kurosawa, S.,Rojas, C.,Yorita, K.,Slusher, B.S.,Fukui, K.,Tsukamoto, T.
Structural basis for potent inhibition of d-amino acid oxidase by thiophene carboxylic acids
Eur J Med Chem, 159:23-34, 2018

PubMed Abstract: A series of thiophene-2-carboxylic acids and thiophene-3-carboxylic acids were identified as a new class of DAO inhibitors. Structure-activity relationship (SAR) studies revealed that small substituents are well-tolerated on the thiophene ring of both the 2-carboxylic acid and 3-carboxylic acid scaffolds. Crystal structures of human DAO in complex with potent thiophene carboxylic acids revealed that Tyr224 was tightly stacked with the thiophene ring of the inhibitors, resulting in the disappearance of the secondary pocket observed with other DAO inhibitors. Molecular dynamics simulations of the complex revealed that Tyr224 preferred the stacked conformation irrespective of whether Tyr224 was stacked or not in the initial state of the simulations. MM/GBSA indicated a substantial hydrophobic interaction between Tyr244 and the thiophene-based inhibitor. In addition, the active site was tightly closed with an extensive network of hydrogen bonds including those from Tyr224 in the stacked conformation. The introduction of a large branched side chain to the thiophene ring markedly decreased potency. These results are in marked contrast to other DAO inhibitors that can gain potency with a branched side chain extending to the secondary pocket due to Tyr224 repositioning. These insights should be of particular importance in future efforts to optimize DAO inhibitors with novel scaffolds.

PubMed: 30265959
DOI: 10.1016/j.ejmech.2018.09.040

実験手法

X-RAY DIFFRACTION (2.6 Å)