6M2B

Crystal structure of human dihydroorotate dehydrogenase (DHODH) with S416

6M2B の概要

• エントリーDOI: 10.2210/pdb6m2b/pdb
• 分子名称: Dihydroorotate dehydrogenase (quinone), mitochondrial, FLAVIN MONONUCLEOTIDE, OROTIC ACID, ... (5 entities in total)
• 機能のキーワード: inhibitor, complex, biosynthetic protein, oxidoreductase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 43620.69

構造登録者

Zhu, L.,Li, H. (登録日: 2020-02-27, 公開日: 2021-03-03, 最終更新日: 2023-11-29)

主引用文献

Xiong, R.,Zhang, L.,Li, S.,Sun, Y.,Ding, M.,Wang, Y.,Zhao, Y.,Wu, Y.,Shang, W.,Jiang, X.,Shan, J.,Shen, Z.,Tong, Y.,Xu, L.,Chen, Y.,Liu, Y.,Zou, G.,Lavillete, D.,Zhao, Z.,Wang, R.,Zhu, L.,Xiao, G.,Lan, K.,Li, H.,Xu, K.
Novel and potent inhibitors targeting DHODH are broad-spectrum antivirals against RNA viruses including newly-emerged coronavirus SARS-CoV-2.
Protein Cell, 11:723-739, 2020

PubMed Abstract: Emerging and re-emerging RNA viruses occasionally cause epidemics and pandemics worldwide, such as the on-going outbreak of the novel coronavirus SARS-CoV-2. Herein, we identified two potent inhibitors of human DHODH, S312 and S416, with favorable drug-likeness and pharmacokinetic profiles, which all showed broad-spectrum antiviral effects against various RNA viruses, including influenza A virus, Zika virus, Ebola virus, and particularly against SARS-CoV-2. Notably, S416 is reported to be the most potent inhibitor so far with an EC of 17 nmol/L and an SI value of 10,505.88 in infected cells. Our results are the first to validate that DHODH is an attractive host target through high antiviral efficacy in vivo and low virus replication in DHODH knock-out cells. This work demonstrates that both S312/S416 and old drugs (Leflunomide/Teriflunomide) with dual actions of antiviral and immuno-regulation may have clinical potentials to cure SARS-CoV-2 or other RNA viruses circulating worldwide, no matter such viruses are mutated or not.

PubMed: 32754890
DOI: 10.1007/s13238-020-00768-w

実験手法

X-RAY DIFFRACTION (1.76 Å)