4dxd: Difference between revisions
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==Staphylococcal Aureus FtsZ in complex with 723== | ==Staphylococcal Aureus FtsZ in complex with 723== | ||
<StructureSection load='4dxd' size='340' side='right' caption='[[4dxd]], [[Resolution|resolution]] 2.01Å' scene=''> | <StructureSection load='4dxd' size='340' side='right'caption='[[4dxd]], [[Resolution|resolution]] 2.01Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4dxd]] is a 1 chain structure with sequence from [ | <table><tr><td colspan='2'>[[4dxd]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Staphylococcus_aureus Staphylococcus aureus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4DXD OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4DXD FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=9PC:3-[(6-CHLORO[1,3]THIAZOLO[5,4-B]PYRIDIN-2-YL)METHOXY]-2,6-DIFLUOROBENZAMIDE'>9PC</scene>, <scene name='pdbligand=GDP:GUANOSINE-5-DIPHOSPHATE'>GDP</scene> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=9PC:3-[(6-CHLORO[1,3]THIAZOLO[5,4-B]PYRIDIN-2-YL)METHOXY]-2,6-DIFLUOROBENZAMIDE'>9PC</scene>, <scene name='pdbligand=GDP:GUANOSINE-5-DIPHOSPHATE'>GDP</scene></td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4dxd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4dxd OCA], [https://pdbe.org/4dxd PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4dxd RCSB], [https://www.ebi.ac.uk/pdbsum/4dxd PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4dxd ProSAT]</span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | |||
</table> | </table> | ||
== Function == | == Function == | ||
[[ | [[https://www.uniprot.org/uniprot/FTSZ_STAAU FTSZ_STAAU]] Essential cell division protein that forms a contractile ring structure (Z ring) at the future cell division site. The regulation of the ring assembly controls the timing and the location of cell division. One of the functions of the FtsZ ring is to recruit other cell division proteins to the septum to produce a new cell wall between the dividing cells. Binds GTP and shows GTPase activity.[HAMAP-Rule:MF_00909] | ||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
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==See Also== | ==See Also== | ||
*[[Cell division protein | *[[Cell division protein 3D structures|Cell division protein 3D structures]] | ||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: | [[Category: Staphylococcus aureus]] | ||
[[Category: | [[Category: Lu J]] | ||
[[Category: | [[Category: Soisson SM]] | ||
Revision as of 11:42, 21 September 2022
Staphylococcal Aureus FtsZ in complex with 723Staphylococcal Aureus FtsZ in complex with 723
Structural highlights
Function[FTSZ_STAAU] Essential cell division protein that forms a contractile ring structure (Z ring) at the future cell division site. The regulation of the ring assembly controls the timing and the location of cell division. One of the functions of the FtsZ ring is to recruit other cell division proteins to the septum to produce a new cell wall between the dividing cells. Binds GTP and shows GTPase activity.[HAMAP-Rule:MF_00909] Publication Abstract from PubMedDespite the need for new antibiotics to treat drug-resistant bacteria, current clinical combinations are largely restricted to beta-lactam antibiotics paired with beta-lactamase inhibitors. We have adapted a Staphylococcus aureus antisense knockdown strategy to genetically identify the cell division Z ring components-FtsA, FtsZ, and FtsW-as beta-lactam susceptibility determinants of methicillin-resistant S. aureus (MRSA). We demonstrate that the FtsZ-specific inhibitor PC190723 acts synergistically with beta-lactam antibiotics in vitro and in vivo and that this combination is efficacious in a murine model of MRSA infection. Fluorescence microscopy localization studies reveal that synergy between these agents is likely to be elicited by the concomitant delocalization of their cognate drug targets (FtsZ and PBP2) in MRSA treated with PC190723. A 2.0 A crystal structure of S. aureus FtsZ in complex with PC190723 identifies the compound binding site, which corresponds to the predominant location of mutations conferring resistance to PC190723 (PC190723(R)). Although structural studies suggested that these drug resistance mutations may be difficult to combat through chemical modification of PC190723, combining PC190723 with the beta-lactam antibiotic imipenem markedly reduced the spontaneous frequency of PC190723(R) mutants. Multiple MRSA PC190723(R) FtsZ mutants also displayed attenuated virulence and restored susceptibility to beta-lactam antibiotics in vitro and in a mouse model of imipenem efficacy. Collectively, these data support a target-based approach to rationally develop synergistic combination agents that mitigate drug resistance and effectively treat MRSA infections. Restoring methicillin-resistant Staphylococcus aureus susceptibility to beta-lactam antibiotics.,Tan CM, Therien AG, Lu J, Lee SH, Caron A, Gill CJ, Lebeau-Jacob C, Benton-Perdomo L, Monteiro JM, Pereira PM, Elsen NL, Wu J, Deschamps K, Petcu M, Wong S, Daigneault E, Kramer S, Liang L, Maxwell E, Claveau D, Vaillancourt J, Skorey K, Tam J, Wang H, Meredith TC, Sillaots S, Wang-Jarantow L, Ramtohul Y, Langlois E, Landry F, Reid JC, Parthasarathy G, Sharma S, Baryshnikova A, Lumb KJ, Pinho MG, Soisson SM, Roemer T Sci Transl Med. 2012 Mar 21;4(126):126ra35. PMID:22440737[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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