| Structural highlights
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).[1] [2] [3] [4] [5] [6] [7] [8]
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[9]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Mazmanian SK, Liu G, Ton-That H, Schneewind O. Staphylococcus aureus sortase, an enzyme that anchors surface proteins to the cell wall. Science. 1999 Jul 30;285(5428):760-3. PMID:10427003
- ↑ Ton-That H, Schneewind O. Anchor structure of staphylococcal surface proteins. IV. Inhibitors of the cell wall sorting reaction. J Biol Chem. 1999 Aug 20;274(34):24316-20. doi: 10.1074/jbc.274.34.24316. PMID:10446208 doi:https://dx.doi.org/10.1074/jbc.274.34.24316
- ↑ Ton-That H, Liu G, Mazmanian SK, Faull KF, Schneewind O. Purification and characterization of sortase, the transpeptidase that cleaves surface proteins of Staphylococcus aureus at the LPXTG motif. Proc Natl Acad Sci U S A. 1999 Oct 26;96(22):12424-9. doi:, 10.1073/pnas.96.22.12424. PMID:10535938 doi:https://dx.doi.org/10.1073/pnas.96.22.12424
- ↑ Mazmanian SK, Liu G, Jensen ER, Lenoy E, Schneewind O. Staphylococcus aureus sortase mutants defective in the display of surface proteins and in the pathogenesis of animal infections. Proc Natl Acad Sci U S A. 2000 May 9;97(10):5510-5. doi: 10.1073/pnas.080520697. PMID:10805806 doi:https://dx.doi.org/10.1073/pnas.080520697
- ↑ Ton-That H, Mazmanian SK, Alksne L, Schneewind O. Anchoring of surface proteins to the cell wall of Staphylococcus aureus. Cysteine 184 and histidine 120 of sortase form a thiolate-imidazolium ion pair for catalysis. J Biol Chem. 2002 Mar 1;277(9):7447-52. doi: 10.1074/jbc.M109945200. Epub 2001, Nov 19. PMID:11714722 doi:https://dx.doi.org/10.1074/jbc.M109945200
- ↑ Perry AM, Ton-That H, Mazmanian SK, Schneewind O. Anchoring of surface proteins to the cell wall of Staphylococcus aureus. III. Lipid II is an in vivo peptidoglycan substrate for sortase-catalyzed surface protein anchoring. J Biol Chem. 2002 May 3;277(18):16241-8. doi: 10.1074/jbc.M109194200. Epub 2002, Feb 20. PMID:11856734 doi:https://dx.doi.org/10.1074/jbc.M109194200
- ↑ Kruger RG, Otvos B, Frankel BA, Bentley M, Dostal P, McCafferty DG. Analysis of the substrate specificity of the Staphylococcus aureus sortase transpeptidase SrtA. Biochemistry. 2004 Feb 17;43(6):1541-51. doi: 10.1021/bi035920j. PMID:14769030 doi:https://dx.doi.org/10.1021/bi035920j
- ↑ Marraffini LA, Ton-That H, Zong Y, Narayana SV, Schneewind O. Anchoring of surface proteins to the cell wall of Staphylococcus aureus. A conserved arginine residue is required for efficient catalysis of sortase A. J Biol Chem. 2004 Sep 3;279(36):37763-70. doi: 10.1074/jbc.M405282200. Epub 2004 , Jul 6. PMID:15247224 doi:https://dx.doi.org/10.1074/jbc.M405282200
- ↑ Jaudzems K, Kurbatska V, Je Kabsons A, Bobrovs R, Rudevica Z, Leonchiks A. Targeting Bacterial Sortase A with Covalent Inhibitors: 27 New Starting Points for Structure-Based Hit-to-Lead Optimization. ACS Infect Dis. 2019 Nov 18. doi: 10.1021/acsinfecdis.9b00265. PMID:31724850 doi:https://dx.doi.org/10.1021/acsinfecdis.9b00265
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