8V04

High resolution TMPRSS2 structure following acylation by nafamostat

8V04 の概要

• エントリーDOI: 10.2210/pdb8v04/pdb
• 分子名称: Transmembrane protease serine 2 non-catalytic chain, Transmembrane protease serine 2, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose, ... (10 entities in total)
• 機能のキーワード: inhibitor complex, protease, viral entry, structural genomics, structural genomics consortium, sgc, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 42238.47

構造登録者

Fraser, B.J.,Dong, A.,Kutera, M.,Seitova, A.,Li, Y.,Hutchinson, A.,Edwards, A.,Benard, F.,Levon, H.,Arrowsmith, C. (登録日: 2023-11-16, 公開日: 2024-01-31, 最終更新日: 2026-01-14)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.58 Å)