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| | <StructureSection load='6un1' size='340' side='right'caption='[[6un1]], [[Resolution|resolution]] 2.26Å' scene=''> | | <StructureSection load='6un1' size='340' side='right'caption='[[6un1]], [[Resolution|resolution]] 2.26Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6un1]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/"bacillus_aeruginosus"_(schroeter_1872)_trevisan_1885 "bacillus aeruginosus" (schroeter 1872) trevisan 1885]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6UN1 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6UN1 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6un1]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Pseudomonas_aeruginosa Pseudomonas aeruginosa]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6UN1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6UN1 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=TJ7:(2R,4S)-2-[(1S)-1-{[(2R)-2-carboxy-2-(thiophen-3-yl)acetyl]amino}-1-methoxy-2-oxoethyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxylic+acid'>TJ7</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.26Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[6un3|6un3]], [[6unb|6unb]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=TJ7:(2~{R},4~{S})-2-[(1~{S})-1-methoxy-2-oxidanylidene-1-[[(2~{R})-3-oxidanyl-3-oxidanylidene-2-thiophen-3-yl-propanoyl]amino]ethyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxylic+acid'>TJ7</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">pbpB, ftsI, ftsI_1, ftsI_2, ALP65_00912, CAZ10_21230, CGU42_01090, DZ934_06595, DZ962_00565, E4V10_06485, EFK68_01815, IPC1492_18840, IPC3_13380, IPC605_16140, IPC669_10550, PAERUG_E15_London_28_01_14_00534, RW109_RW109_05757 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=287 "Bacillus aeruginosus" (Schroeter 1872) Trevisan 1885])</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=6un1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6un1 OCA], [https://pdbe.org/6un1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6un1 RCSB], [https://www.ebi.ac.uk/pdbsum/6un1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6un1 ProSAT]</span></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Serine-type_D-Ala-D-Ala_carboxypeptidase Serine-type D-Ala-D-Ala carboxypeptidase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.16.4 3.4.16.4] </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=6un1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6un1 OCA], [http://pdbe.org/6un1 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6un1 RCSB], [http://www.ebi.ac.uk/pdbsum/6un1 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6un1 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/FTSI_PSEAE FTSI_PSEAE] Catalyzes cross-linking of the peptidoglycan cell wall at the division septum (By similarity). Binds penicillin (PubMed:20580675).[HAMAP-Rule:MF_02080]<ref>PMID:20580675</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </StructureSection> | | </StructureSection> |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Serine-type D-Ala-D-Ala carboxypeptidase]] | + | [[Category: Pseudomonas aeruginosa]] |
| - | [[Category: Chen, Y]] | + | [[Category: Chen Y]] |
| - | [[Category: Sacco, M]] | + | [[Category: Sacco M]] |
| - | [[Category: B-lactam]]
| + | |
| - | [[Category: High-molecular mass]]
| + | |
| - | [[Category: Hmm]]
| + | |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Lactam]]
| + | |
| - | [[Category: Penicillin]]
| + | |
| - | [[Category: Penicillin-binding protein 3]]
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| - | [[Category: Pseudomonas aeruginosa pbp3]]
| + | |
| - | [[Category: Temocillin]]
| + | |
| - | [[Category: Ticarcillin]]
| + | |
| - | [[Category: Transpeptidase]]
| + | |
| Structural highlights
Function
FTSI_PSEAE Catalyzes cross-linking of the peptidoglycan cell wall at the division septum (By similarity). Binds penicillin (PubMed:20580675).[HAMAP-Rule:MF_02080][1]
Publication Abstract from PubMed
The prevalence of multi-drug resistant Pseudomonas aeruginosa has led to the re-examination of older 'forgotten' drugs, such as temocillin, for their ability to combat resistant microbes. Temocillin is the 6-alpha-methoxy analogue of ticarcillin, a carboxypenicillin with well characterized antipseudomonal properties. The alpha-methoxy modification confers resistance to serine beta-lactamases, yet temocillin is ineffective against P. aeruginosa growth. The origins of temocillin's inferior antibacterial properties against P. aeruginosa have remained relatively unexplored. Here we analyze the reaction kinetics, protein stability, and binding conformations of temocillin and ticarcillin with penicillin-binding protein 3 (PBP3), an essential PBP in P. aeruginosa We show the 6-alpha-methoxy group perturbs the stability of the PBP3 acyl-enzyme, which manifests in an elevated koff in biochemical assays comparing temocillin with ticarcillin. Complex crystal structures with PBP3 reveal similar binding modes of the two drugs, but with important differences. Most notably, the 6-alpha-methoxy group disrupts a high-quality hydrogen bond with a conserved residue important for ligand binding, while also being inserted into a crowded active site, possibly destabilizing the active site and enabling water molecule from bulk solvent to access and cleave the acyl-enzyme bond. This hypothesis is supported by the observation that the acyl-enzyme complex of temocillin has reduced thermal stability compared with ticarcillin. Furthermore, we explore temocillin's mechanism of beta-lactamase inhibition with a high-resolution complex structure of CTX-M-14 class A serine beta-lactamase. The results suggest the alpha-methoxy group prevents hydrolysis by locking the compound into an unexpected conformation that impedes access of the catalytic water to the acyl-enzyme adduct.
Influence of the alpha-methoxy group on the reaction of temocillin with Pseudomonas aeruginosa PBP3 and CTX-M-14 beta-lactamase.,Sacco MD, Kroeck KG, Kemp MT, Zhang X, Andrews LD, Chen Y Antimicrob Agents Chemother. 2019 Nov 4. pii: AAC.01473-19. doi:, 10.1128/AAC.01473-19. PMID:31685462[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ de Leon SR, Daniels K, Clarke AJ. Production and purification of the penicillin-binding protein 3 from Pseudomonas aeruginosa. Protein Expr Purif. 2010 Oct;73(2):177-83. doi: 10.1016/j.pep.2010.05.005. Epub, 2010 May 16. PMID:20580675 doi:http://dx.doi.org/10.1016/j.pep.2010.05.005
- ↑ Sacco MD, Kroeck KG, Kemp MT, Zhang X, Andrews LD, Chen Y. Influence of the alpha-methoxy group on the reaction of temocillin with Pseudomonas aeruginosa PBP3 and CTX-M-14 beta-lactamase. Antimicrob Agents Chemother. 2019 Nov 4. pii: AAC.01473-19. doi:, 10.1128/AAC.01473-19. PMID:31685462 doi:http://dx.doi.org/10.1128/AAC.01473-19
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