6r1v
From Proteopedia
(Difference between revisions)
| Line 1: | Line 1: | ||
| - | '''Unreleased structure''' | ||
| - | + | ==Solution structure of sortase A from S. aureus in complex with 2-(aminomethyl)-3-hydroxy-4H-pyran-4-one based prodrug== | |
| + | <StructureSection load='6r1v' size='340' side='right'caption='[[6r1v]], [[NMR_Ensembles_of_Models | 20 NMR models]]' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[6r1v]] is a 1 chain structure. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6R1V OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6R1V FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=JPT:6-(hydroxymethyl)-3-oxidanyl-2-(thiophen-3-ylmethyl)pyran-4-one'>JPT</scene></td></tr> | ||
| + | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Sortase_A Sortase A], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.22.70 3.4.22.70] </span></td></tr> | ||
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6r1v FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6r1v OCA], [http://pdbe.org/6r1v PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6r1v RCSB], [http://www.ebi.ac.uk/pdbsum/6r1v PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6r1v ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [[http://www.uniprot.org/uniprot/SRTA_STAA8 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).<ref>PMID:10427003</ref> <ref>PMID:10446208</ref> <ref>PMID:10535938</ref> <ref>PMID:10805806</ref> <ref>PMID:11714722</ref> <ref>PMID:11856734</ref> <ref>PMID:14769030</ref> <ref>PMID:15247224</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == 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<ref>PMID:31724850</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| + | <div class="pdbe-citations 6r1v" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Sortase A]] | ||
[[Category: Jaudzems, K]] | [[Category: Jaudzems, K]] | ||
[[Category: Leonchiks, A]] | [[Category: Leonchiks, A]] | ||
| + | [[Category: Covalent complex]] | ||
| + | [[Category: Hydrolase]] | ||
| + | [[Category: Inhibitor]] | ||
| + | [[Category: Prodrug]] | ||
Revision as of 16:16, 22 January 2020
Solution structure of sortase A from S. aureus in complex with 2-(aminomethyl)-3-hydroxy-4H-pyran-4-one based prodrug
| |||||||||||
