{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Fraser BJ"],"funding":["Killam doctoral Fellowship. Mitacs Elevate postdoctoral fellowship","NIAID NIH HHS","U.S. Department of Health & Human Services | National Institutes of Health (NIH)","Wellcome Trust","U.S. Department of Health & Human Services | National Institutes of Health"],"pagination":["4351"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC12065894"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["16(1)"],"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 "],"journal":["Nature communications"],"pubmed_title":["Structural basis of TMPRSS11D specificity and autocleavage activation."],"pmcid":["PMC12065894"],"funding_grant_id":["U19 AI171292","1U19AI171292-01"],"pubmed_authors":["Ilyassov O","Leduc R","Fraser BJ","Lac J","Seitova A","Hejazi Z","Arrowsmith CH","Ferkova S","Benard F","Wilson RP","Boudreault PL","Edwards A","Li Y","Penn LZ","Morin GB","Kenney TMG","Dong A","Li YY"],"additional_accession":[]},"is_claimable":false,"name":"Structural basis of TMPRSS11D specificity and autocleavage activation.","description":"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 ","dates":{"release":"2025-01-01T00:00:00Z","publication":"2025 May","modification":"2026-06-02T20:48:31.952Z","creation":"2026-04-20T03:14:30.436Z"},"accession":"S-EPMC12065894","cross_references":{"pubmed":["40348740"],"doi":["10.1038/s41467-025-59677-3"]}}