8W3C
Crystal Structure of Enterovirus 68 3C Protease with AG7088 at 1.97 Angstroms
Summary for 8W3C
| Entry DOI | 10.2210/pdb8w3c/pdb |
| Descriptor | Peptidase C3, 4-{2-(4-FLUORO-BENZYL)-6-METHYL-5-[(5-METHYL-ISOXAZOLE-3-CARBONYL)-AMINO]-4-OXO-HEPTANOYLAMINO}-5-(2-OXO-PYRROLIDIN-3-YL)-PENTANOIC ACID ETHYL ESTER (3 entities in total) |
| Functional Keywords | protease, hydrolase, enterovirus, 3c protein, ev68, inhibitor, viral protein, hydrolase-inhibitor complex, hydrolase/inhibitor |
| Biological source | enterovirus D68 |
| Total number of polymer chains | 1 |
| Total formula weight | 21763.70 |
| Authors | Azzolino, V.N.,Shaqra, A.M.,Schiffer, C.A. (deposition date: 2024-02-22, release date: 2025-01-15, Last modification date: 2025-02-05) |
| Primary citation | Azzolino, V.N.,Shaqra, A.M.,Ali, A.,Kurt Yilmaz, N.,Schiffer, C.A. Structural Analysis of Inhibitor Binding to Enterovirus-D68 3C Protease. Viruses, 17:-, 2025 Cited by PubMed Abstract: Enterovirus-D68 (EV68) continues to present as a global health issue causing respiratory illness and outbreaks associated with long-lasting neurological disease, with no antivirals or specific treatment options. The development of antiviral therapeutics, such as small-molecule inhibitors that target conserved proteins like the enteroviral 3C protease, remains to be achieved. While various 3C inhibitors have been investigated, their design does not consider the potential emergence of drug resistance mutations. For other antivirals where resistance has been a challenge, we have demonstrated that the likelihood of resistance can be minimized by designing inhibitors that leverage the evolutionary constraints of the target. Here, we characterize a series of 3C inhibitors against EV68-3C protease through enzyme inhibition, protein crystallography, and structural analysis. We have determined and analyzed three high-resolution inhibitor-bound crystal structures of EV68-3C protease, which revealed possible sites of resistance mutations, a key structural water molecule conserved during ligand binding, and the conformational flexibility of the catalytic histidine H40. This structural analysis combined with enzymatic assays provides insights for the rational design of inhibitors that are robust against resistance toward developing antiviral treatments for EV68 infections. PubMed: 39861864DOI: 10.3390/v17010075 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.97 Å) |
Structure validation
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