8W3C

Crystal Structure of Enterovirus 68 3C Protease with AG7088 at 1.97 Angstroms

8W3C の概要

• エントリーDOI: 10.2210/pdb8w3c/pdb
• 分子名称: 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)
• 機能のキーワード: protease, hydrolase, enterovirus, 3c protein, ev68, inhibitor, viral protein, hydrolase-inhibitor complex, hydrolase/inhibitor
• 由来する生物種: enterovirus D68
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 21763.70

構造登録者

Azzolino, V.N.,Shaqra, A.M.,Schiffer, C.A. (登録日: 2024-02-22, 公開日: 2025-01-15, 最終更新日: 2025-02-05)

主引用文献

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

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: 39861864
DOI: 10.3390/v17010075

実験手法

X-RAY DIFFRACTION (1.97 Å)