4LCH

Crystal structure of the Pseudomonas aeruginosa LPXC/LPC-051 complex

4LCH の概要

• エントリーDOI: 10.2210/pdb4lch/pdb
• 関連するPDBエントリー: 4LCF 4LCG
• 分子名称: UDP-3-O-[3-hydroxymyristoyl] N-acetylglucosamine deacetylase, ZINC ION, (betaS)-Nalpha-{4-[4-(4-aminophenyl)buta-1,3-diyn-1-yl]benzoyl}-N,beta-dihydroxy-beta-methyl-L-tyrosinamide, ... (5 entities in total)
• 機能のキーワード: lipid a biosynthesis, lipid a synthesis, baab sandwich, lpxc, deacetylation, acyl udp-glcnac, hydroxamate, hydrolase-antibiotic complex, hydrolase/antibiotic
• 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: 34804.41

構造登録者

Lee, C.-J.,Zhou, P. (登録日: 2013-06-21, 公開日: 2013-08-21, 最終更新日: 2024-02-28)

主引用文献

Liang, X.,Lee, C.J.,Zhao, J.,Toone, E.J.,Zhou, P.
Synthesis, Structure, and Antibiotic Activity of Aryl-Substituted LpxC Inhibitors.
J.Med.Chem., 56:6954-6966, 2013

PubMed Abstract: The zinc-dependent deacetylase LpxC catalyzes the committed step of lipid A biosynthesis in Gram-negative bacteria and is a validated target for the development of novel antibiotics to combat multidrug-resistant Gram-negative infections. Many potent LpxC inhibitors contain an essential threonyl-hydroxamate headgroup for high-affinity interaction with LpxC. We report the synthesis, antibiotic activity, and structural and enzymatic characterization of novel LpxC inhibitors containing an additional aryl group in the threonyl-hydroxamate moiety, which expands the inhibitor-binding surface in LpxC. These compounds display enhanced potency against LpxC in enzymatic assays and superior antibiotic activity against Francisella novicida in cell culture. The comparison of the antibiotic activities of these compounds against a leaky Escherichia coli strain and the wild-type strain reveals the contribution of the formidable outer-membrane permeability barrier that reduces the compounds efficacy in cell culture and emphasizes the importance of maintaining a balanced hydrophobicity and hydrophilicity profile in developing effective LpxC-targeting antibiotics.

PubMed: 23914798
DOI: 10.1021/jm4007774

実験手法

X-RAY DIFFRACTION (1.596 Å)