6U4P

Structure-based discovery of a novel small-molecule inhibitor of methicillin-resistant S. aureus

6U4P の概要

• エントリーDOI: 10.2210/pdb6u4p/pdb
• 関連するPDBエントリー: 6U3T 6U49
• 分子名称: Alpha-hemolysin, fos-choline-14, SULFATE ION, ... (4 entities in total)
• 機能のキーワード: alpha-toxin, pvl, leukocidins, mrsa, toxin
• 由来する生物種: Staphylococcus aureus
• タンパク質・核酸の鎖数: 7
• 化学式量合計: 241057.91

構造登録者

Liu, J.,Kozhaya, L.,Torres, V.J.,Unutmaz, D.,Lu, M. (登録日: 2019-08-26, 公開日: 2020-03-25, 最終更新日: 2023-10-11)

主引用文献

Liu, J.,Kozhaya, L.,Torres, V.J.,Unutmaz, D.,Lu, M.
Structure-based discovery of a small-molecule inhibitor of methicillin-resistantStaphylococcus aureusvirulence.
J.Biol.Chem., 295:5944-5959, 2020

PubMed Abstract: The rapid emergence and dissemination of methicillin-resistant (MRSA) strains poses a major threat to public health. MRSA possesses an arsenal of secreted host-damaging virulence factors that mediate pathogenicity and blunt immune defenses. Panton-Valentine leukocidin (PVL) and α-toxin are exotoxins that create lytic pores in the host cell membrane. They are recognized as being important for the development of invasive MRSA infections and are thus potential targets for antivirulence therapies. Here, we report the high-resolution X-ray crystal structures of both PVL and α-toxin in their soluble, monomeric, and oligomeric membrane-inserted pore states in complex with -tetradecylphosphocholine (CPC). The structures revealed two evolutionarily conserved phosphatidylcholine-binding mechanisms and their roles in modulating host cell attachment, oligomer assembly, and membrane perforation. Moreover, we demonstrate that the soluble CPC compound protects primary human immune cells against cytolysis by PVL and α-toxin and hence may serve as the basis for the development of an antivirulence agent for managing MRSA infections.

PubMed: 32179646
DOI: 10.1074/jbc.RA120.012697

実験手法

X-RAY DIFFRACTION (2.49 Å)