6S3A

Coxsackie B3 2C protein in complex with S-Fluoxetine

6S3A の概要

• エントリーDOI: 10.2210/pdb6s3a/pdb
• 分子名称: 2C protein, (3S)-N-methyl-3-phenyl-3-[4-(trifluoromethyl)phenoxy]propan-1-amine, ZINC ION, ... (5 entities in total)
• 機能のキーワード: 2c, enterovirus, helicase, atpase, complex, antiviral, porzac, fluoxetine, repurposing, coxsackievirus, viral protein
• 由来する生物種: Coxsackievirus B3
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 24173.55

構造登録者

El Kazzi, P.,Papageorgiou, N.,Ferron, F.P.,Bauer, L.,van Kuppeveld, F.,Coutard, B. (登録日: 2019-06-24, 公開日: 2021-01-13, 最終更新日: 2024-06-19)

主引用文献

Hurdiss, D.L.,El Kazzi, P.,Bauer, L.,Papageorgiou, N.,Ferron, F.P.,Donselaar, T.,van Vliet, A.L.W.,Shamorkina, T.M.,Snijder, J.,Canard, B.,Decroly, E.,Brancale, A.,Zeev-Ben-Mordehai, T.,Forster, F.,van Kuppeveld, F.J.M.,Coutard, B.
Fluoxetine targets an allosteric site in the enterovirus 2C AAA+ ATPase and stabilizes a ring-shaped hexameric complex.
Sci Adv, 8:eabj7615-eabj7615, 2022

PubMed Abstract: Enteroviruses are globally prevalent human pathogens responsible for many diseases. The nonstructural protein 2C is a AAA+ helicase and plays a key role in enterovirus replication. Drug repurposing screens identified 2C-targeting compounds such as fluoxetine and dibucaine, but how they inhibit 2C is unknown. Here, we present a crystal structure of the soluble and monomeric fragment of coxsackievirus B3 2C protein in complex with ()-fluoxetine (SFX), revealing an allosteric binding site. To study the functional consequences of SFX binding, we engineered an adenosine triphosphatase (ATPase)–competent, hexameric 2C protein. Using this system, we show that SFX, dibucaine, HBB [2-(α-hydroxybenzyl)-benzimidazole], and guanidine hydrochloride inhibit 2C ATPase activity. Moreover, cryo–electron microscopy analysis demonstrated that SFX and dibucaine lock 2C in a defined hexameric state, rationalizing their mode of inhibition. Collectively, these results provide important insights into 2C inhibition and a robust engineering strategy for structural, functional, and drug-screening analysis of 2C proteins.

PubMed: 34985963
DOI: 10.1126/sciadv.abj7615

実験手法

X-RAY DIFFRACTION (1.52 Å)