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TitleFluoxetine targets an allosteric site in the enterovirus 2C AAA+ ATPase and stabilizes a ring-shaped hexameric complex.
Journal, issue, pagesSci Adv, Vol. 8, Issue 1, Page eabj7615, Year 2022
Publish dateJan 7, 2022
AuthorsDaniel L Hurdiss / Priscila El Kazzi / Lisa Bauer / Nicolas Papageorgiou / François P Ferron / Tim Donselaar / Arno L W van Vliet / Tatiana M Shamorkina / Joost Snijder / Bruno Canard / Etienne Decroly / Andrea Brancale / Tzviya Zeev-Ben-Mordehai / Friedrich Förster / Frank J M van Kuppeveld / Bruno Coutard /
PubMed AbstractEnteroviruses 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 ...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.
External linksSci Adv / PubMed:34985963 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution1.52 - 12.0 Å
Structure data

EMDB-12798:
Hexameric coxsackievirus B3 2C protein in complex with S-fluoxetine
Method: EM (single particle) / Resolution: 12.0 Å

PDB-6s3a:
Coxsackie B3 2C protein in complex with S-Fluoxetine
Method: X-RAY DIFFRACTION / Resolution: 1.52 Å

PDB-6t3w:
Coxsackie B3 2C protein in complex with S-Fluoxetine
Method: X-RAY DIFFRACTION / Resolution: 1.82 Å

Chemicals

ChemComp-SFX:
(3S)-N-methyl-3-phenyl-3-[4-(trifluoromethyl)phenoxy]propan-1-amine / antidepressant, inhibitor*YM / Fluoxetine

ChemComp-ZN:
Unknown entry

ChemComp-CL:
Unknown entry / Chloride

ChemComp-HOH:
WATER / Water

ChemComp-SO4:
SULFATE ION / Sulfate

ChemComp-NA:
Unknown entry

Source
  • Coxsackievirus B3 (strain Nancy)
  • coxsackievirus b3
KeywordsVIRAL PROTEIN / 2C / enterovirus / helicase / ATPase / complex / antiviral / Porzac / fluoxetine / repurposing / coxsackievirus

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