9shr | pdb_00009shr

Alpha-Hemolysin of S.aureus (monomer) in complex with the small molecule N-(3-(Diethylamino)propyl)-1-(6-(p-tolyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidine-4-carboxamide

spinqualitylabelsall models 9shr, resolution 2.08Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9shr is a 1 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 2.08Å Ligands: A1JN0, NA, SO4, TRS Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function HLA_STAA8 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 (By similarity). Publication Abstract from PubMed Staphylococcus aureus is a major human pathogen responsible for severe infections that necessitate alternative therapeutic strategies. Its key virulence factor alpha-hemolysin (Hla) mediates host cell damage via pore formation, making it an attractive target for antivirulence interventions. Here, we report the development of a high-throughput cellular assay measuring toxin-induced calcium influx. Its application led to the identification of thiadiazole-based small molecule inhibitors of Hla. Structure-activity relationship studies with 18 analogs led to inhibitors with a cellular potency up to 5.4 microM. X-ray crystallography of Hla in complex with compound 1 revealed that the thiadiazole bound a hydrophobic pocket at the interface of the amino latch and prestem domains, exerting a dual mechanism that blocks stem loop unfolding as well as membrane attachment. These findings introduce thiadiazoles as a novel chemical class of antivirulence therapeutics against S. aureus infections. An Imidazo[2,1-b][1,3,4]thiadiazole Derivative Inhibits the Virulence Factor alpha-Hemolysin by Blocking the Pullout of Its Stem Domain.,Korotkov VS, Lukat P, Di Lucrezia R, Shekhar A, Degenhart C, Diestel R, Bilitewski U, Dinkel K, Blankenfeldt W, Bronstrup M ChemMedChem. 2026 Feb 25;21(4):e202501098. doi: 10.1002/cmdc.202501098. PMID:41725408 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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