6r1v

Solution structure of sortase A from S. aureus in complex with 2-(aminomethyl)-3-hydroxy-4H-pyran-4-one based prodrug

spinqualitylabelsall models 6r1v Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6r1v is a 1 chain structure with sequence from Staphylococcus aureus subsp. aureus NCTC 8325. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Solution NMR, 20 models Ligands: JPT Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function SRTA_STAA8 Transpeptidase that anchors surface proteins to the cell wall (PubMed:10427003, PubMed:10446208, PubMed:10535938, PubMed:11714722, PubMed:14769030, PubMed:15247224). Recognizes and modifies its substrate by proteolytic cleavage of a C-terminal sorting signal. Following cleavage, a covalent intermediate is formed via a thioester bond between the sortase and its substrate, which is then transferred and covalently attached to the cell wall (PubMed:10446208, PubMed:10535938, PubMed:11714722, PubMed:14769030, PubMed:15247224). This sortase recognizes a Leu-Pro-x-Thr-Gly (LPXTG) motif, which is cleaved by the sortase between the threonine and glycine residues (PubMed:10535938, PubMed:11714722, PubMed:14769030, PubMed:15247224). Utilizes lipid II as the peptidoglycan substrate for the sorting reaction (PubMed:10446208, PubMed:11856734). Responsible for the display of important virulence factors (PubMed:14769030). Important for interactions with the host and host colonization during infection (PubMed:10805806, PubMed:14769030). Publication Abstract from PubMed Because of its essential role as a bacterial virulence factor, enzyme sortase A (SrtA) has become an attractive target for the development of new antivirulence drugs against Gram-positive infections. Here we describe 27 compounds identified as covalent inhibitors of Staphylococcus aureus SrtA by screening a library of approximately 50000 compounds using a FRET assay followed by NMR-based validation and binding reversibility analysis. Nineteen of these compounds displayed only moderate to weak cytotoxicity, with CC50 against NIH 3T3 mice fibroblast cells ranging from 12 to 740 muM. Analysis using covalent docking suggests that the inhibitors initially associate via hydrophobic interactions, followed by covalent bond formation between the SrtA active site cysteine and an electrophilic center of the inhibitor. The compounds represent good starting points that have the potential to be developed into broad spectrum antivirulence agents as exemplified by hit-to-lead optimization of one of the compounds. Targeting Bacterial Sortase A with Covalent Inhibitors: 27 New Starting Points for Structure-Based Hit-to-Lead Optimization.,Jaudzems K, Kurbatska V, Je Kabsons A, Bobrovs R, Rudevica Z, Leonchiks A ACS Infect Dis. 2019 Nov 18. doi: 10.1021/acsinfecdis.9b00265. PMID:31724850 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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