2. Academic Validation
  3. Structure and activity of human TMPRSS2 protease implicated in SARS-CoV-2 activation

Structure and activity of human TMPRSS2 protease implicated in SARS-CoV-2 activation

  • Nat Chem Biol. 2022 Sep;18(9):963-971. doi: 10.1038/s41589-022-01059-7.
Bryan J Fraser  # 1 2,  Serap Beldar  # 3,  Almagul Seitova 3,  Ashley Hutchinson 3,  Dhiraj Mannar 4,  Yanjun Li 3,  Daniel Kwon 1 2,  Ruiyan Tan 1,  Ryan P Wilson 1,  Karoline Leopold 4,  Sriram Subramaniam 4,  Levon Halabelian 5 6,  Cheryl H Arrowsmith 7 8 9,  François Bénard 10 11
Affiliations

Affiliations

  • 1 Department of Molecular Oncology, British Columbia Cancer Research Institute, Vancouver, British Columbia, Canada.
  • 2 Department of Radiology, University of British Columbia, Vancouver, British Columbia, Canada.
  • 3 Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada.
  • 4 Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia, Canada.
  • 5 Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada. L.halabelian@utoronto.ca.
  • 6 Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada. L.halabelian@utoronto.ca.
  • 7 Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada. Cheryl.arrowsmith@uhnresearch.ca.
  • 8 Princess Margaret Cancer Centre, Toronto, Ontario, Canada. Cheryl.arrowsmith@uhnresearch.ca.
  • 9 Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. Cheryl.arrowsmith@uhnresearch.ca.
  • 10 Department of Molecular Oncology, British Columbia Cancer Research Institute, Vancouver, British Columbia, Canada. fbenard@bccrc.ca.
  • 11 Department of Radiology, University of British Columbia, Vancouver, British Columbia, Canada. fbenard@bccrc.ca.
  • # Contributed equally.
PMID: 35676539 DOI: 10.1038/s41589-022-01059-7
Abstract

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 Å 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 µM and determined inhibitor mechanisms of action, providing the groundwork for drug development efforts to selectively inhibit TMPRSS2.

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