9DPF

Crystal structure of TMPRSS11D S368A complexed with its own zymogen activation motif

9DPF の概要

• エントリーDOI: 10.2210/pdb9dpf/pdb
• 分子名称: Transmembrane protease serine 11D, Transmembrane protease serine 11D non-catalytic chain, 1,2-ETHANEDIOL, ... (4 entities in total)
• 機能のキーワード: hydrolase, human protease, zymogen motif
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 54621.45

構造登録者

Fraser, B.J.,Dong, A.,Ilyassov, O.,Seitova, A.,Li, Y.,Edwards, A.,Benard, F.,Arrowsmith, C.,Structural Genomics Consortium (SGC) (登録日: 2024-09-21, 公開日: 2024-10-16, 最終更新日: 2025-05-28)

主引用文献

Fraser, B.J.,Wilson, R.P.,Ferkova, S.,Ilyassov, O.,Lac, J.,Dong, A.,Li, Y.Y.,Seitova, A.,Li, Y.,Hejazi, Z.,Kenney, T.M.G.,Penn, L.Z.,Edwards, A.,Leduc, R.,Boudreault, P.L.,Morin, G.B.,Benard, F.,Arrowsmith, C.H.
Structural basis of TMPRSS11D specificity and autocleavage activation.
Nat Commun, 16:4351-4351, 2025

PubMed Abstract: Transmembrane Protease, Serine-2 (TMPRSS2) and TMPRSS11D are human proteases that enable SARS-CoV-2 and Influenza A/B virus infections, but their biochemical mechanisms for facilitating viral cell entry remain unclear. We show these proteases spontaneously and efficiently cleave their own zymogen activation motifs, activating their broader protease activity on cellular substrates. We determine TMPRSS11D co-crystal structures with a native and an engineered activation motif, revealing insights into its autocleavage activation and distinct substrate binding cleft features. Leveraging this structural data, we develop nanomolar potency peptidomimetic inhibitors of TMPRSS11D and TMPRSS2. We show that a broad serine protease inhibitor that underwent clinical trials for TMPRSS2-targeted COVID-19 therapy, nafamostat mesylate, was rapidly cleaved by TMPRSS11D and converted to low activity derivatives. In this work, we develop mechanistic insights into human protease viral tropism and highlight both the strengths and limitations of existing human serine protease inhibitors, informing future drug discovery efforts targeting these proteases.

PubMed: 40348740
DOI: 10.1038/s41467-025-59677-3

実験手法

X-RAY DIFFRACTION (1.9 Å)