6U49
Structure-based discovery of a novel small-molecule inhibitor of methicillin-resistant S. aureus
Summary for 6U49
| Entry DOI | 10.2210/pdb6u49/pdb |
| Related | 6U3T |
| Descriptor | Alpha-hemolysin, fos-choline-14, SULFATE ION, ... (4 entities in total) |
| Functional Keywords | alpha-toxin, pvl, leukocidins, mrsa, toxin |
| Biological source | Staphylococcus aureus |
| Total number of polymer chains | 7 |
| Total formula weight | 241501.30 |
| Authors | Liu, J.,Kozhaya, L.,Torres, V.J.,Unutmaz, D.,Lu, M. (deposition date: 2019-08-23, release date: 2020-03-25, Last modification date: 2023-10-11) |
| Primary citation | 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 Cited by 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: 32179646DOI: 10.1074/jbc.RA120.012697 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.35 Å) |
Structure validation
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