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| | <StructureSection load='7jwl' size='340' side='right'caption='[[7jwl]], [[Resolution|resolution]] 2.20Å' scene=''> | | <StructureSection load='7jwl' size='340' side='right'caption='[[7jwl]], [[Resolution|resolution]] 2.20Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[7jwl]] is a 1 chain structure with sequence from [https://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=7JWL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7JWL FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[7jwl]] 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=7JWL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7JWL FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=VMM:ETX0462+(Bound+form)'>VMM</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]] 2.2Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">pbpB, ftsI, ftsI_2, ALP65_00912, CAZ10_21230, CGU42_01090, DZ934_06595, DZ962_00565, E4V10_06485, ECC04_026610, ERJ99_003095, FCG96_14995, FLI88_02250, IPC1481_11065, IPC1482_17070, IPC165_24935, IPC170_23205, IPC669_10550, RW109_RW109_05757 ([https://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='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=VMM:ETX0462+(Bound+form)'>VMM</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Serine-type_D-Ala-D-Ala_carboxypeptidase Serine-type D-Ala-D-Ala carboxypeptidase], with EC number [https://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'>[https://proteopedia.org/fgij/fg.htm?mol=7jwl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7jwl OCA], [https://pdbe.org/7jwl PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7jwl RCSB], [https://www.ebi.ac.uk/pdbsum/7jwl PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7jwl ProSAT]</span></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=7jwl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7jwl OCA], [https://pdbe.org/7jwl PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7jwl RCSB], [https://www.ebi.ac.uk/pdbsum/7jwl PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7jwl 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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| | </div> | | </div> |
| | <div class="pdbe-citations 7jwl" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 7jwl" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Penicillin-binding protein 3D structures|Penicillin-binding protein 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
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| | </StructureSection> | | </StructureSection> |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Serine-type D-Ala-D-Ala carboxypeptidase]] | |
| - | [[Category: Abendroth, J]] | |
| - | [[Category: Durand-Reville, T F]] | |
| - | [[Category: Horanyi, P S]] | |
| - | [[Category: Mayclin, S J]] | |
| - | [[Category: Moussa, S]] | |
| - | [[Category: Shapiro, A]] | |
| - | [[Category: Sylvester, M]] | |
| - | [[Category: Wu, X]] | |
| - | [[Category: Antibiotic]] | |
| - | [[Category: Etx0462]] | |
| - | [[Category: Pbp3]] | |
| | [[Category: Pseudomonas aeruginosa]] | | [[Category: Pseudomonas aeruginosa]] |
| | + | [[Category: Abendroth J]] |
| | + | [[Category: Durand-Reville TF]] |
| | + | [[Category: Horanyi PS]] |
| | + | [[Category: Mayclin SJ]] |
| | + | [[Category: Moussa S]] |
| | + | [[Category: Shapiro A]] |
| | + | [[Category: Sylvester M]] |
| | + | [[Category: Wu X]] |
| 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 development of new antibiotics to treat infections caused by drug-resistant Gram-negative pathogens is of paramount importance as antibiotic resistance continues to increase worldwide(1). Here we describe a strategy for the rational design of diazabicyclooctane inhibitors of penicillin-binding proteins from Gram-negative bacteria to overcome multiple mechanisms of resistance, including beta-lactamase enzymes, stringent response and outer membrane permeation. Diazabicyclooctane inhibitors retain activity in the presence of beta-lactamases, the primary resistance mechanism associated with beta-lactam therapy in Gram-negative bacteria(2,3). Although the target spectrum of an initial lead was successfully re-engineered to gain in vivo efficacy, its ability to permeate across bacterial outer membranes was insufficient for further development. Notably, the features that enhanced target potency were found to preclude compound uptake. An improved optimization strategy leveraged porin permeation properties concomitant with biochemical potency in the lead-optimization stage. This resulted in ETX0462, which has potent in vitro and in vivo activity against Pseudomonas aeruginosa plus all other Gram-negative ESKAPE pathogens, Stenotrophomonas maltophilia and biothreat pathogens. These attributes, along with a favourable preclinical safety profile, hold promise for the successful clinical development of the first novel Gram-negative chemotype to treat life-threatening antibiotic-resistant infections in more than 25 years.
Rational design of a new antibiotic class for drug-resistant infections.,Durand-Reville TF, Miller AA, O'Donnell JP, Wu X, Sylvester MA, Guler S, Iyer R, Shapiro AB, Carter NM, Velez-Vega C, Moussa SH, McLeod SM, Chen A, Tanudra AM, Zhang J, Comita-Prevoir J, Romero JA, Huynh H, Ferguson AD, Horanyi PS, Mayclin SJ, Heine HS, Drusano GL, Cummings JE, Slayden RA, Tommasi RA Nature. 2021 Sep 15. pii: 10.1038/s41586-021-03899-0. doi:, 10.1038/s41586-021-03899-0. PMID:34526714[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
- ↑ Durand-Reville TF, Miller AA, O'Donnell JP, Wu X, Sylvester MA, Guler S, Iyer R, Shapiro AB, Carter NM, Velez-Vega C, Moussa SH, McLeod SM, Chen A, Tanudra AM, Zhang J, Comita-Prevoir J, Romero JA, Huynh H, Ferguson AD, Horanyi PS, Mayclin SJ, Heine HS, Drusano GL, Cummings JE, Slayden RA, Tommasi RA. Rational design of a new antibiotic class for drug-resistant infections. Nature. 2021 Sep 15. pii: 10.1038/s41586-021-03899-0. doi:, 10.1038/s41586-021-03899-0. PMID:34526714 doi:http://dx.doi.org/10.1038/s41586-021-03899-0
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