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Fluoxetine targets an allosteric site in the enterovirus 2C AAA+ ATPase and stabilizes a ring-shaped hexameric complex

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 (S)-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-(-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.
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https://hal.archives-ouvertes.fr/hal-03572836
Contributor : François Ferron Connect in order to contact the contributor
Submitted on : Monday, February 14, 2022 - 2:04:44 PM
Last modification on : Wednesday, May 11, 2022 - 10:00:05 AM
Long-term archiving on: : Sunday, May 15, 2022 - 6:57:54 PM

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Daniel L Hurdiss, Priscila El Kazzi, Lisa Bauer, Nicolas Papageorgiou, Francois Ferron, et al.. Fluoxetine targets an allosteric site in the enterovirus 2C AAA+ ATPase and stabilizes a ring-shaped hexameric complex. Science Advances , American Association for the Advancement of Science (AAAS), 2022, 8 (1), ⟨10.1126/sciadv.abj7615⟩. ⟨hal-03572836⟩

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