6F8B

LasB bound to thiol based inhibitor

6F8B の概要

• エントリーDOI: 10.2210/pdb6f8b/pdb
• 分子名称: Elastase, CALCIUM ION, ZINC ION, ... (5 entities in total)
• 機能のキーワード: lasb, inhibitor, 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: 33753.25

構造登録者

Koehnke, J.,Sikandar, A. (登録日: 2017-12-12, 公開日: 2018-03-28, 最終更新日: 2024-11-06)

主引用文献

Kany, A.M.,Sikandar, A.,Haupenthal, J.,Yahiaoui, S.,Maurer, C.K.,Proschak, E.,Kohnke, J.,Hartmann, R.W.
Binding Mode Characterization and Early in Vivo Evaluation of Fragment-Like Thiols as Inhibitors of the Virulence Factor LasB from Pseudomonas aeruginosa.
ACS Infect Dis, 4:988-997, 2018

PubMed Abstract: The increasing emergence of antibiotic resistance necessitates the development of anti-infectives with novel modes of action. Targeting bacterial virulence is considered a promising approach to develop novel antibiotics with reduced selection pressure. The extracellular collagenase elastase (LasB) plays a pivotal role in the infection process of Pseudomonas aeruginosa and therefore represents an attractive antivirulence target. Mercaptoacetamide-based thiols have been reported to inhibit LasB as well as collagenases from clostridia and bacillus species. The present work provides an insight into the structure-activity relationship (SAR) of these fragment-like LasB inhibitors, demonstrating an inverse activity profile compared to similar inhibitors of clostridial collagenase H (ColH). An X-ray cocrystal structure is presented, revealing distinct binding of two compounds to the active site of LasB, which unexpectedly maintains an open conformation. We further demonstrate in vivo efficacy in a Galleria mellonella infection model and high selectivity of the LasB inhibitors toward human matrix metalloproteinases (MMPs).

PubMed: 29485268
DOI: 10.1021/acsinfecdis.8b00010

実験手法

X-RAY DIFFRACTION (1.3 Å)