Journal
NATURE CHEMICAL BIOLOGY
Volume 18, Issue 9, Pages 963-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41589-022-01059-7
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Funding
- BC Leadership Chair in Functional Cancer Imaging
- Canadian Institute of Health Research grant [FDN154328]
- Canada Excellence Research Chair
- National Institute of General Medical Sciences from the National Institutes of Health [P30 GM124165]
- NIH-ORIP HEI grant [S10OD021527]
- DOE Office of Science [DE-AC02-06CH11357]
- Boehringer Ingelheim
- Bristol Myers Squibb
- Genome Canada through Ontario Genomics Institute [OGI-196]
- EU
- EFPIA through the Innovative Medicines Initiative 2 Joint Undertaking [875510]
- Janssen
- Merck KGaA
- Pfizer
- Takeda
- Bayer AG
- Genentech
- Mitacs Accelerate Internship
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This study provides insights into the structure and function of TMPRSS2, a key protein involved in the viral entry and pathogenesis of SARS-CoV-2. By studying its structure and cleavage sites, the researchers also uncovered the specificity of TMPRSS2, which can aid in drug development efforts.
Transmembrane protease, serine 2 (TMPRSS2) has been identified as key host cell factor for viral entry and pathogenesis of SARS-CoV-2. Specifically, TMPRSS2 proteolytically processes the SARS-CoV-2 Spike (S) protein, enabling virus-host membrane fusion and infection of the airways. We present here a recombinant production strategy for enzymatically active TMPRSS2 and characterization of its matured proteolytic activity, as well as its 1.95 angstrom X-ray cocrystal structure with the synthetic protease inhibitor nafamostat. Our study provides a structural basis for the potent but nonspecific inhibition by nafamostat and identifies distinguishing features of the TMPRSS2 substrate binding pocket that explain specificity. TMPRSS2 cleaved SARS-CoV-2 S protein at multiple sites, including the canonical S1/S2 cleavage site. We ranked the potency of clinical protease inhibitors with half-maximal inhibitory concentrations ranging from 1.4 nM to 120 mu M and determined inhibitor mechanisms of action, providing the groundwork for drug development efforts to selectively inhibit TMPRSS2.
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