Summary for 9H0X
| Entry DOI | 10.2210/pdb9h0x/pdb |
| Descriptor | 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) |
| Functional Keywords | inhibitor, proa, legionella pneumophila, antibiotics, hydrolase |
| Biological source | Legionella pneumophila str. Corby |
| Total number of polymer chains | 1 |
| Total formula weight | 38334.72 |
| Authors | |
| Primary citation | 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 Cited by 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: 40479898DOI: 10.1016/j.ejmech.2025.117832 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.36 Å) |
Structure validation
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