9E83

TMPRSS2 crystal structure following acylation by UCSF_157

Summary for 9E83

• Entry DOI: 10.2210/pdb9e83/pdb
• Descriptor: Transmembrane protease serine 2, Transmembrane protease serine 2 non-catalytic chain, CITRIC ACID, ... (7 entities in total)
• Functional Keywords: trypsin-like serine protease, antiviral target, viral entry, hydrolase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 40692.87

Authors

Fraser, B.J.,Dong, A.,Seitova, A.,Li, Y.,Hutchinson, A.,Young, N.,Bender, B.,Gahbauer, S.,Edwards, A.,Shoichet, B.,Craik, C.,Arrowsmith, C.H. (deposition date: 2024-11-04, release date: 2024-12-25, 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

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: 40973081
DOI: 10.1021/acs.jmedchem.4c03089

Experimental method

X-RAY DIFFRACTION (2.07 Å)