9H0X

ProA in complex with inhibitor 6

これはPDB形式変換不可エントリーです。

9H0X の概要

• エントリーDOI: 10.2210/pdb9h0x/pdb
• 分子名称: Zinc metalloproteinase, (2~{R})-2-(2-methylpropyl)-~{N}-[4-[[4-[(2-methylpropylsulfonylamino)methyl]-1,2,3-triazol-1-yl]methyl]phenyl]-~{N}'-oxidanyl-propanediamide, ZINC ION, ... (4 entities in total)
• 機能のキーワード: inhibitor, proa, legionella pneumophila, antibiotics, hydrolase
• 由来する生物種: Legionella pneumophila str. Corby
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 38334.72

構造登録者

Ornago, C.,Blankenfeldt, W. (登録日: 2024-10-09, 公開日: 2025-06-18)

主引用文献

Scheithauer, L.,Ornago, C.,Selmar, J.,Schutz, C.,Bianchi, G.,Kiefer, A.,Haupenthal, J.,Dellmann, A.,Huynh, D.,Zhang, R.,Blankenfeldt, W.,Hirsch, A.H.,Steinert, M.
Innovative zinc-binding inhibitors of Legionella pneumophila ProA reduce collagen and flagellin degradation, TLR5 evasion, and human lung tissue inflammation.
Eur.J.Med.Chem., 296:117832-117832, 2025

PubMed Abstract: Legionnaires' disease is a severe pneumonia caused by the aquatic bacterium Legionella pneumophila. In recent years, the number of cases has continuously increased according to the distribution of aerosol-producing technologies, global warming, and demographic ageing, which elevates bacterial transmission, environmental cell counts and host susceptibility. Despite the availability of an antibiotic therapy, this treatment cannot eradicate the risk of irreversible symptoms or high mortality rates. The bacterial zinc metalloprotease ProA significantly contributes to life-threatening tissue damage in patients and hence promotes progression of the disease. We hypothesize that additional application of an inhibitory agent against this protease may reduce serious complications and the risk of respiratory failure until successful bacterial clearance. Here we present a newly designed set of zinc-binding compounds and evaluated their inhibitory effects on the versatile physiological activity of ProA during infection. We identified a potent phosphonate inhibitor, which reduces ProA-dependent cleavage of host collagen IV and bacterial flagellin, immune evasion from the TLR5-NF-κB pathway and PMN-mediated inflammation in human lung tissue explants (HLTEs). Based on efficacy at the biochemical, cellular and tissue levels and the results of ProA co-crystallizations, we conclude that the selected inhibitors represent promising lead structures for the future development of clinically applicable pathoblockers against Legionnaires' disease.

PubMed: 40479898
DOI: 10.1016/j.ejmech.2025.117832

実験手法

X-RAY DIFFRACTION (1.36 Å)