6u4p

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

spinqualitylabelsall models 6u4p, resolution 2.49Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6u4p is a 7 chain structure with sequence from Staphylococcus aureus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.49Å Ligands: PQJ, SO4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function HLA_STAAU Alpha-toxin binds to the membrane of eukaryotic cells resulting in the release of low-molecular weight molecules and leading to an eventual osmotic lysis. Heptamer oligomerization and pore formation is required for lytic activity. Publication Abstract from PubMed The rapid emergence and dissemination of methicillin-resistant Staphylococcus aureus (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 alpha-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 alpha-toxin in their soluble, monomeric and oligomeric membrane-inserted pore states in complex with n-tetradecylphosphocholine (C14PC). 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 C14PC compound protects primary human immune cells in vitro against cytolysis by PVL and alpha-toxin and hence may serve as the basis for the development of an antivirulence agent for managing MRSA infections. Structure-based discovery of a small-molecule inhibitor of methicillin-resistant Staphylococcus aureus virulence.,Liu J, Kozhaya L, Torres VJ, Unutmaz D, Lu M J Biol Chem. 2020 Mar 16. pii: RA120.012697. doi: 10.1074/jbc.RA120.012697. PMID:32179646 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Hemolysin 3D structures

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