Structural basis of TMPRSS11D specificity and autocleavage activation

Bryan J. Fraser (), Ryan P. Wilson, Sára Ferková, Olzhas Ilyassov, Jackie Lac, Aiping Dong, Yen-Yen Li, Alma Seitova, Yanjun Li, Zahra Hejazi, Tristan M. G. Kenney, Linda Z. Penn, Aled Edwards, Richard Leduc, Pierre-Luc Boudreault, Gregg B. Morin (), François Bénard () and Cheryl H. Arrowsmith ()
Additional contact information
Bryan J. Fraser: Structural Genomics Consortium Toronto
Ryan P. Wilson: Structural Genomics Consortium Toronto
Sára Ferková: Université de Sherbrooke
Olzhas Ilyassov: Structural Genomics Consortium Toronto
Jackie Lac: Structural Genomics Consortium Toronto
Aiping Dong: Structural Genomics Consortium Toronto
Yen-Yen Li: Structural Genomics Consortium Toronto
Alma Seitova: Structural Genomics Consortium Toronto
Yanjun Li: Structural Genomics Consortium Toronto
Zahra Hejazi: Structural Genomics Consortium Toronto
Tristan M. G. Kenney: University of Toronto
Linda Z. Penn: University of Toronto
Aled Edwards: Structural Genomics Consortium Toronto
Richard Leduc: Université de Sherbrooke
Pierre-Luc Boudreault: Université de Sherbrooke
Gregg B. Morin: Canada’s Michael Smith Genome Sciences Centre
François Bénard: British Columbia Cancer Research Institute
Cheryl H. Arrowsmith: Structural Genomics Consortium Toronto

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-59677-3

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