7MEQ

Crystal structure of human TMPRSS2 in complex with Nafamostat

7MEQ の概要

• エントリーDOI: 10.2210/pdb7meq/pdb
• 分子名称: 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)
• 機能のキーワード: covid19, protease, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 44496.89

構造登録者

Fraser, B.,Beldar, S.,Hutchinson, A.,Li, Y.,Seitova, A.,Edwards, A.M.,Benard, F.,Arrowsmith, C.H.,Halabelian, L.,Structural Genomics Consortium (SGC) (登録日: 2021-04-07, 公開日: 2021-04-21, 最終更新日: 2024-10-16)

主引用文献

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

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: 35676539
DOI: 10.1038/s41589-022-01059-7

実験手法

X-RAY DIFFRACTION (1.95 Å)