6FZX

LasB, hydroxymate Inhibitor Complex

6FZX の概要

• エントリーDOI: 10.2210/pdb6fzx/pdb
• 分子名称: Keratinase KP2, ~{N}-(3,4-dichlorophenyl)-~{N}'-oxidanyl-propanediamide, ZINC ION, ... (7 entities in total)
• 機能のキーワード: lasb, hydroxymate inhibitor complex, hydrolase
• 由来する生物種: Pseudomonas aeruginosa
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 33732.25

構造登録者

Koehnke, J.,Sikandar, A. (登録日: 2018-03-15, 公開日: 2018-09-05, 最終更新日: 2024-11-13)

主引用文献

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

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: 30088919
DOI: 10.1021/acschembio.8b00257

実験手法

X-RAY DIFFRACTION (2.1 Å)