6FZX
LasB, hydroxymate Inhibitor Complex
Summary for 6FZX
| Entry DOI | 10.2210/pdb6fzx/pdb |
| Descriptor | Keratinase KP2, ~{N}-(3,4-dichlorophenyl)-~{N}'-oxidanyl-propanediamide, ZINC ION, ... (7 entities in total) |
| Functional Keywords | lasb, hydroxymate inhibitor complex, hydrolase |
| Biological source | Pseudomonas aeruginosa |
| Total number of polymer chains | 1 |
| Total formula weight | 33732.25 |
| Authors | Koehnke, J.,Sikandar, A. (deposition date: 2018-03-15, release date: 2018-09-05, Last modification date: 2024-11-13) |
| Primary citation | Kany, A.M.,Sikandar, A.,Yahiaoui, S.,Haupenthal, J.,Walter, I.,Empting, M.,Kohnke, J.,Hartmann, R.W. Tackling Pseudomonas aeruginosa Virulence by a Hydroxamic Acid-Based LasB Inhibitor. ACS Chem. Biol., 13:2449-2455, 2018 Cited by PubMed Abstract: In search of novel antibiotics to combat the challenging spread of resistant pathogens, bacterial proteases represent promising targets for pathoblocker development. A common motif for protease inhibitors is the hydroxamic acid function, yet this group has often been related to unspecific inhibition of various metalloproteases. In this work, the inhibition of LasB, a harmful zinc metalloprotease secreted by Pseudomonas aeruginosa, through a hydroxamate derivative is described. The present inhibitor was developed based on a recently reported, highly selective thiol scaffold. Using X-ray crystallography, the lack of inhibition of a range of human matrix metalloproteases could be attributed to a distinct binding mode sparing the S1' pocket. The inhibitor was shown to restore the effect of the antimicrobial peptide LL-37, decrease the formation of P. aeruginosa biofilm and, for the first time for a LasB inhibitor, reduce the release of extracellular DNA. Hence, it is capable of disrupting several important bacterial resistance mechanisms. These results highlight the potential of protease inhibitors to fight bacterial infections and point out the possibility to achieve selective inhibition even with a strong zinc anchor. PubMed: 30088919DOI: 10.1021/acschembio.8b00257 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.1 Å) |
Structure validation
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