8FL5

Crystal Structure of Enterovirus 68 3C Protease inactive mutant C147A at 1.8 Angstroms.

8FL5 の概要

• エントリーDOI: 10.2210/pdb8fl5/pdb
• 分子名称: 3C Protease (2 entities in total)
• 機能のキーワード: protease, hydrolase, enterovirus, 3c protein, ev68, inactive mutant, viral protein
• 由来する生物種: enterovirus D68
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 40395.84

構造登録者

Azzolino, V.N.,Shaqra, A.M.,Schiffer, C.A. (登録日: 2022-12-21, 公開日: 2024-01-10, 最終更新日: 2024-10-09)

主引用文献

Azzolino, V.N.,Shaqra, A.M.,Ali, A.,Kurt Yilmaz, N.,Schiffer, C.A.
Elucidating the Substrate Envelope of Enterovirus 68-3C Protease: Structural Basis of Specificity and Potential Resistance.
Viruses, 16:-, 2024

PubMed Abstract: Enterovirus-D68 (EV68) has emerged as a global health concern over the last decade with severe symptomatic infections resulting in long-lasting neurological deficits and death. Unfortunately, there are currently no FDA-approved antiviral drugs for EV68 or any other non-polio enterovirus. One particularly attractive class of potential drugs are small molecules inhibitors, which can target the conserved active site of EV68-3C protease. For other viral proteases, we have demonstrated that the emergence of drug resistance can be minimized by designing inhibitors that leverage the evolutionary constraints of substrate specificity. However, the structural characterization of EV68-3C protease bound to its substrates has been lacking. Here, we have determined the substrate specificity of EV68-3C protease through molecular modeling, molecular dynamics (MD) simulations, and co-crystal structures. Molecular models enabled us to successfully characterize the conserved hydrogen-bond networks between EV68-3C protease and the peptides corresponding to the viral cleavage sites. In addition, co-crystal structures we determined have revealed substrate-induced conformational changes of the protease which involved new interactions, primarily surrounding the S1 pocket. We calculated the substrate envelope, the three-dimensional consensus volume occupied by the substrates within the active site. With the elucidation of the EV68-3C protease substrate envelope, we evaluated how 3C protease inhibitors, AG7088 and SG-85, fit within the active site to predict potential resistance mutations.

PubMed: 39339895
DOI: 10.3390/v16091419

実験手法

X-RAY DIFFRACTION (1.8 Å)