9D9Y

Human norovirus GI.1 Norwalk protease in complex with rupintrivir

9D9Y の概要

• エントリーDOI: 10.2210/pdb9d9y/pdb
• 分子名称: 3C-like protease, 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: viral protease with inhibitor, viral protein
• 由来する生物種: Norovirus
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 39821.72

構造登録者

Zhao, B.,Pham, S.H.,Neetu, N.,Sankaran, B.,Prasad, B.V.V. (登録日: 2024-08-21, 公開日: 2025-02-19, 最終更新日: 2025-03-12)

主引用文献

Pham, S.,Zhao, B.,Neetu, N.,Sankaran, B.,Patil, K.,Ramani, S.,Song, Y.,Estes, M.K.,Palzkill, T.,Prasad, B.V.V.
Conformational flexibility is a critical factor in designing broad-spectrum human norovirus protease inhibitors.
J.Virol., 99:e0175724-e0175724, 2025

PubMed Abstract: Human norovirus (HuNoV) is a leading cause of gastroenteritis worldwide and is associated with significant morbidity, mortality, and economic impact. There are currently no licensed antiviral drugs for the treatment of HuNoV-associated gastroenteritis. The HuNoV protease plays a critical role in the initiation of virus replication by cleaving the polyprotein. Thus, it is an ideal target for developing antiviral small-molecule inhibitors. While rupintrivir, a potent small-molecule inhibitor of several picornavirus proteases, effectively inhibits GI.1 protease, it is an order of magnitude less effective against GII protease. Other GI.1 protease inhibitors also tend to be less effective against GII proteases. To understand the structural basis for the potency difference, we determined the crystal structures of proteases of GI.1, pandemic GII.4 (Houston and Sydney), and GII.3 in complex with rupintrivir. These structures show that the open substrate pocket in GI protease binds rupintrivir without requiring significant conformational changes, whereas, in GII proteases, the closed pocket flexibly extends, reorienting arginine-112 in the BII-CII loop to accommodate rupintrivir. Structures of R112A protease mutants with rupintrivir, coupled with enzymatic and inhibition studies, suggest R112 is involved in displacing both substrate and ligands from the active site, implying a role in the release of cleaved products during polyprotein processing. Thus, the primary determinant for differential inhibitor potency between the GI and GII proteases is the increased flexibility in the BII-CII loop of the GII proteases caused by the H-G mutation in this loop. Therefore, the inherent flexibility of the BII-CII loop in GII proteases is a critical factor to consider when developing broad-spectrum inhibitors for HuNoV proteases.

PubMed: 39873493
DOI: 10.1128/jvi.01757-24

実験手法

X-RAY DIFFRACTION (1.8 Å)