8FRO

Acinetobacter baylyi LptB2FG bound to lipopolysaccharide and a macrocyclic peptide

8FRO の概要

• エントリーDOI: 10.2210/pdb8fro/pdb
• EMDBエントリー: 29400 29401 29402 29403 29404
• 分子名称: Lipopolysaccharide export system ATP-binding protein LptB, Lipopolysaccharide export system permease protein LptF, LPS export ABC transporter permease LptG, ... (5 entities in total)
• 機能のキーワード: lipopolysaccharide, abc, atpase, antibiotic, macrocyclic peptide, gram-negative bacteria, eskape, lipid transport
• 由来する生物種: Acinetobacter baylyi ADP1; 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 143424.52

構造登録者

Pahil, K.S.,Gilman, M.S.A.,Kruse, A.C.,Kahne, D. (登録日: 2023-01-07, 公開日: 2024-01-03, 最終更新日: 2024-01-31)

主引用文献

Pahil, K.S.,Gilman, M.S.A.,Baidin, V.,Clairfeuille, T.,Mattei, P.,Bieniossek, C.,Dey, F.,Muri, D.,Baettig, R.,Lobritz, M.,Bradley, K.,Kruse, A.C.,Kahne, D.
A new antibiotic traps lipopolysaccharide in its intermembrane transporter.
Nature, 625:572-577, 2024

PubMed Abstract: Gram-negative bacteria are extraordinarily difficult to kill because their cytoplasmic membrane is surrounded by an outer membrane that blocks the entry of most antibiotics. The impenetrable nature of the outer membrane is due to the presence of a large, amphipathic glycolipid called lipopolysaccharide (LPS) in its outer leaflet. Assembly of the outer membrane requires transport of LPS across a protein bridge that spans from the cytoplasmic membrane to the cell surface. Maintaining outer membrane integrity is essential for bacterial cell viability, and its disruption can increase susceptibility to other antibiotics. Thus, inhibitors of the seven lipopolysaccharide transport (Lpt) proteins that form this transenvelope transporter have long been sought. A new class of antibiotics that targets the LPS transport machine in Acinetobacter was recently identified. Here, using structural, biochemical and genetic approaches, we show that these antibiotics trap a substrate-bound conformation of the LPS transporter that stalls this machine. The inhibitors accomplish this by recognizing a composite binding site made up of both the Lpt transporter and its LPS substrate. Collectively, our findings identify an unusual mechanism of lipid transport inhibition, reveal a druggable conformation of the Lpt transporter and provide the foundation for extending this class of antibiotics to other Gram-negative pathogens.

PubMed: 38172635
DOI: 10.1038/s41586-023-06799-7

実験手法

ELECTRON MICROSCOPY (3.25 Å)