8V1F
TMPRSS2 complexed with the noncovalent inhibitor 6-amidino-2-napthol
Summary for 8V1F
| Entry DOI | 10.2210/pdb8v1f/pdb |
| Descriptor | Transmembrane protease serine 2 non-catalytic chain, CITRIC ACID, TETRAETHYLENE GLYCOL, ... (12 entities in total) |
| Functional Keywords | inhibitor complex, protease, viral entry, structural genomics, structural genomics consortium, sgc, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 4 |
| Total formula weight | 84383.08 |
| Authors | Fraser, B.J.,Dong, A.,Kutera, M.,Seitova, A.,Li, Y.,Hutchinson, A.,Edwards, A.,Benard, F.,Halabelian, L.,Arrowsmith, C.,Structural Genomics Consortium (SGC) (deposition date: 2023-11-20, release date: 2024-02-07, Last modification date: 2026-01-14) |
| Primary citation | Fraser, B.J.,Young, N.J.,Bender, B.J.,Gahbauer, S.,Ilyassov, O.,Wilson, R.P.,Li, Y.,Seitova, A.,Lourenco, A.L.,Chung, D.H.,Bardine, C.,Benard, F.,Shoichet, B.K.,Craik, C.S.,Arrowsmith, C.H. Large Library Docking and Biophysical Analysis of Small-Molecule TMPRSS2 Inhibitors. J.Med.Chem., 68:19893-19907, 2025 Cited by PubMed Abstract: Transmembrane protease serine-2 (TMPRSS2) is an essential host entry factor in human airways for SARS-CoV-2 and influenza A/B and has presented as a target for antiviral drug development; however, no clinically viable oral small-molecule TMPRSS2 inhibitors have been developed to date. Here, we perform two large-scale docking campaigns to identify covalent and noncovalent TMPRSS2 small-molecule inhibitors using a homology model and crystal structure. We establish a pipeline to rapidly screen TMPRSS2 inhibitors and then interrogate the potency, selectivity, and biophysical properties of covalent and noncovalent inhibition using enzyme kinetics on synthetic peptide and protein substrates and differential scanning fluorimetry. Furthermore, we established a readily crystallizable form of TMPRSS2 protein that produced high-resolution crystal structures with , , and . A novel noncovalent inhibitor scaffold is biochemically validated as a potential avenue for developing TMPRSS2-selective inhibitors. PubMed: 40973081DOI: 10.1021/acs.jmedchem.4c03089 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.19 Å) |
Structure validation
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