6T3W
Coxsackie B3 2C protein in complex with S-Fluoxetine
Summary for 6T3W
| Entry DOI | 10.2210/pdb6t3w/pdb |
| Descriptor | 2C protein, ZINC ION, SULFATE ION, ... (6 entities in total) |
| Functional Keywords | 2c, enterovirus, helicase, atpase, complex, antiviral, porzac, fluoxetine, repurposing, coxsackievirus, viral protein |
| Biological source | Coxsackievirus B3 |
| Total number of polymer chains | 1 |
| Total formula weight | 24568.33 |
| Authors | El Kazzi, P.,Papageorgiou, N.,Ferron, F.P.,Bauer, L.,van Kuppeveld, F.,Coutard, B. (deposition date: 2019-10-11, release date: 2020-11-18, Last modification date: 2024-06-19) |
| Primary citation | 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 Cited by 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: 34985963DOI: 10.1126/sciadv.abj7615 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.82 Å) |
Structure validation
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