4IGH

High resolution crystal structure of human dihydroorotate dehydrogenase bound with 4-quinoline carboxylic acid analog

4IGH の概要

• エントリーDOI: 10.2210/pdb4igh/pdb
• 分子名称: Dihydroorotate dehydrogenase (quinone), mitochondrial, FLAVIN MONONUCLEOTIDE, OROTIC ACID, ... (7 entities in total)
• 機能のキーワード: anti-viral, quinoline-4-carboxylic acid, redox, dehydrogenase, fmn, membrane, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Mitochondrion inner membrane; Single-pass membrane protein: Q02127
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 42143.88

構造登録者

Deng, X.,Das, P.,Fontoura, B.M.A.,Phillips, M.A.,De Brabander, J.K. (登録日: 2012-12-17, 公開日: 2013-08-21, 最終更新日: 2023-09-20)

主引用文献

Das, P.,Deng, X.,Zhang, L.,Roth, M.G.,Fontoura, B.M.,Phillips, M.A.,De Brabander, J.K.
SAR Based Optimization of a 4-Quinoline Carboxylic Acid Analog with Potent Anti-Viral Activity.
ACS MED.CHEM.LETT., 4:517-521, 2013

PubMed Abstract: It is established that drugs targeting viral proteins are at risk of generating resistant strains. However, drugs targeting host factors can potentially avoid this problem. Herein we report structure-activity relationship studies leading to the discovery of a very potent lead compound 6-fluoro-2-(5-isopropyl-2-methyl-4-phenoxyphenyl)quinoline-4-carboxylic acid () that inhibits human dihydroorotate dehydrogenase (DHODH) with an IC of 1 nM, and viral replication of VSV and WSN-Influenza with an EC of 2 nM and 41 nM. We also solved the X-ray structure of human DHODH bound to , providing structural insight into the potent inhibition of biaryl ether analogs of brequinar.

PubMed: 23930152
DOI: 10.1021/ml300464h

実験手法

X-RAY DIFFRACTION (1.3 Å)