6ftb

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Current revision (22:14, 9 August 2018) (edit) (undo)
 
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<StructureSection load='6ftb' size='340' side='right' caption='[[6ftb]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
<StructureSection load='6ftb' size='340' side='right' caption='[[6ftb]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[6ftb]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6FTB OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6FTB FirstGlance]. <br>
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<table><tr><td colspan='2'>[[6ftb]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Staphylococcus_aureus_mw2 Staphylococcus aureus mw2]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6FTB OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6FTB FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1QW:(2R)-2,3-DIHYDROXYPROPYL+DODECANOATE'>1QW</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=M0E:MOENOMYCIN'>M0E</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1QW:(2R)-2,3-DIHYDROXYPROPYL+DODECANOATE'>1QW</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=M0E:MOENOMYCIN'>M0E</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3hzs|3hzs]], [[2c6w|2c6w]], [[2zc5|2zc5]], [[2olu|2olu]], [[3dwk|3dwk]], [[2olv|2olv]]</td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3hzs|3hzs]], [[2c6w|2c6w]], [[2zc5|2zc5]], [[2olu|2olu]], [[3dwk|3dwk]], [[2olv|2olv]]</td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">mgt, MW1814 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1242971 Staphylococcus aureus MW2])</td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Peptidoglycan_glycosyltransferase Peptidoglycan glycosyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.4.1.129 2.4.1.129] </span></td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Peptidoglycan_glycosyltransferase Peptidoglycan glycosyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.4.1.129 2.4.1.129] </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=6ftb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ftb OCA], [http://pdbe.org/6ftb PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ftb RCSB], [http://www.ebi.ac.uk/pdbsum/6ftb PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ftb ProSAT]</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=6ftb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ftb OCA], [http://pdbe.org/6ftb PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ftb RCSB], [http://www.ebi.ac.uk/pdbsum/6ftb PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ftb ProSAT]</span></td></tr>
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<div style="background-color:#fffaf0;">
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
== Publication Abstract from PubMed ==
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Bacterial cell wall transglycosylases (TGs) and transpeptidases (TPs) are ideal drug targets due to their essentiality, accessibility and lack of mammalian homologs. Although antibacterial therapy using the beta-lactam family of TP inhibitors has been successful for decades, potent TG inhibitors which are suitable for development into antibiotics for human use have yet to be identified. We sought to further understand the molecular interactions required to inhibit bacterial transglycosylation by characterizing the active site of Staphylococcus aureus (Sa) monofunctional transglycosylase (Mtg). Ten mutants were tested for their ability to polymerize Lipid II and to crystallize in the presence of moenomycin. Five of six putative active site mutants (E100Q, D101N, Q136E, E156T, and Y176F) were found to be catalytically inactive whereas a F104Y mutation did not affect activity. Four mutants generated to enhance crystal formation (F143T, V154T, L157T, and F158T) also retained activity. Here we also report the crystal structure of Sa Mtg E100Q mutant in complex with the inhibitor moenomycin to 2.1A resolution. The co-crystal structure revealed detailed interactions between the protein and inhibitor including portions of the polycarbon tail of moenomycin. The structure also contained an ordered phosphate ion which helped to identify the Lipid II binding site.
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Bacterial peptidoglycan glycosyltransferases (PGT) catalyse the essential polymerization of lipid II into linear glycan chains required for peptidoglycan biosynthesis. The PGT domain is composed of a large head subdomain and a smaller jaw subdomain and can be potently inhibited by the antibiotic moenomycin A (MoeA). We present an X-ray structure of the MoeA-bound Staphylococcus aureus monofunctional PGT enzyme, revealing electron density for a second MoeA bound to the jaw subdomain as well as the PGT donor site. Isothermal titration calorimetry confirms two drug-binding sites with markedly different affinities and positive cooperativity. Hydrophobic cluster analysis suggests that the membrane-interacting surface of the jaw subdomain has structural and physicochemical properties similar to amphipathic cationic alpha -helical antimicrobial peptides for lipid II recognition and binding. Furthermore, molecular dynamics simulations of the drug-free and -bound forms of the enzyme demonstrate the importance of the jaw subdomain movement for lipid II selection and polymerization process and provide molecular-level insights into the mechanism of peptidoglycan biosynthesis by PGTs.
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Characterization of the active site of S. aureus monofunctional glycosyltransferase (Mtg) by site-directed mutation and structural analysis of the protein complexed with moenomycin.,Heaslet H, Shaw B, Mistry A, Miller AA J Struct Biol. 2009 Aug;167(2):129-35. Epub 2009 May 3. PMID:19416756<ref>PMID:19416756</ref>
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The role of the jaw subdomain of peptidoglycan glycosyltransferases for lipid II polymerization.,Punekar AS, Samsudin F, Lloyd AJ, Dowson CG, Scott DJ, Khalid S, Roper DI Cell Surf. 2018 Jun;2:54-66. doi: 10.1016/j.tcsw.2018.06.002. PMID:30046666<ref>PMID:30046666</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</StructureSection>
</StructureSection>
[[Category: Peptidoglycan glycosyltransferase]]
[[Category: Peptidoglycan glycosyltransferase]]
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[[Category: Staphylococcus aureus mw2]]
[[Category: Dowson, C J]]
[[Category: Dowson, C J]]
[[Category: Punekar, A S]]
[[Category: Punekar, A S]]

Current revision

Staphylococcus aureus monofunctional glycosyltransferase in complex with moenomycin

6ftb, resolution 2.10Å

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