7MEQ
Crystal structure of human TMPRSS2 in complex with Nafamostat
Summary for 7MEQ
| Entry DOI | 10.2210/pdb7meq/pdb |
| Descriptor | Transmembrane protease serine 2, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, 4-carbamimidamidobenzoic acid, ... (5 entities in total) |
| Functional Keywords | covid19, protease, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 44496.89 |
| Authors | Fraser, B.,Beldar, S.,Hutchinson, A.,Li, Y.,Seitova, A.,Edwards, A.M.,Benard, F.,Arrowsmith, C.H.,Halabelian, L.,Structural Genomics Consortium (SGC) (deposition date: 2021-04-07, release date: 2021-04-21, Last modification date: 2024-10-16) |
| Primary citation | Fraser, B.J.,Beldar, S.,Seitova, A.,Hutchinson, A.,Mannar, D.,Li, Y.,Kwon, D.,Tan, R.,Wilson, R.P.,Leopold, K.,Subramaniam, S.,Halabelian, L.,Arrowsmith, C.H.,Benard, F. Structure and activity of human TMPRSS2 protease implicated in SARS-CoV-2 activation. Nat.Chem.Biol., 18:963-971, 2022 Cited by PubMed 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. PubMed: 35676539DOI: 10.1038/s41589-022-01059-7 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.95 Å) |
Structure validation
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