Structure and activity of human TMPRSS2 protease implicated in SARS-CoV-2 activation.
Journal
Nature chemical biology
ISSN: 1552-4469
Titre abrégé: Nat Chem Biol
Pays: United States
ID NLM: 101231976
Informations de publication
Date de publication:
09 2022
09 2022
Historique:
received:
24
08
2021
accepted:
09
05
2022
pubmed:
9
6
2022
medline:
25
8
2022
entrez:
8
6
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 35676539
doi: 10.1038/s41589-022-01059-7
pii: 10.1038/s41589-022-01059-7
doi:
Substances chimiques
Spike Glycoprotein, Coronavirus
0
spike protein, SARS-CoV-2
0
Peptide Hydrolases
EC 3.4.-
Serine Endopeptidases
EC 3.4.21.-
TMPRSS2 protein, human
EC 3.4.21.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
963-971Subventions
Organisme : CIHR
ID : FDN154328
Pays : Canada
Organisme : NIGMS NIH HHS
ID : P30 GM124165
Pays : United States
Organisme : NIH HHS
ID : S10 OD021527
Pays : United States
Informations de copyright
© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.
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