4ool: Difference between revisions
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==Crystal structure of PBP3 in complex with compound 14 ((2E)-2-({[(2S)-2-{[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-{[(1,5-dihydroxy-4-oxo-1,4-dihydropyridin-2-yl)methoxy]imino}acetyl]amino}-3-oxopropyl]oxy}imino)pentanedioic acid)== | |||
<StructureSection load='4ool' size='340' side='right'caption='[[4ool]], [[Resolution|resolution]] 2.30Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4ool]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Pseudomonas_aeruginosa_PA1R Pseudomonas aeruginosa PA1R]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4OOL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4OOL FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.3Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2U2:(2E)-2-({[(2S)-2-{[(2Z)-2-(2-AMINO-1,3-THIAZOL-4-YL)-2-{[(1,5-DIHYDROXY-4-OXO-1,4-DIHYDROPYRIDIN-2-YL)METHOXY]IMINO}ACETYL]AMINO}-3-OXOPROPYL]OXY}IMINO)PENTANEDIOIC+ACID'>2U2</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=4ool FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ool OCA], [https://pdbe.org/4ool PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4ool RCSB], [https://www.ebi.ac.uk/pdbsum/4ool PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4ool ProSAT]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Multidrug-resistant Gram-negative pathogens are an emerging threat to human health, and addressing this challenge will require development of new antibacterial agents. This can be achieved through an improved molecular understanding of drug-target interactions combined with enhanced delivery of these agents to the site of action. Herein we describe the first application of siderophore receptor-mediated drug uptake of lactivicin analogues as a strategy that enables the development of novel antibacterial agents against clinically relevant Gram-negative bacteria. We report the first crystal structures of several sideromimic conjugated compounds bound to penicillin binding proteins PBP3 and PBP1a from Pseudomonas aeruginosa and characterize the reactivity of lactivicin and beta-lactam core structures. Results from drug sensitivity studies with beta-lactamase enzymes are presented, as well as a structure-based hypothesis to reduce susceptibility to this enzyme class. Finally, mechanistic studies demonstrating that sideromimic modification alters the drug uptake process are discussed. | |||
Siderophore Receptor-Mediated Uptake of Lactivicin Analogues in Gram-Negative Bacteria.,Starr J, Brown MF, Aschenbrenner L, Caspers N, Che Y, Gerstenberger BS, Huband M, Knafels JD, Lemmon MM, Li C, McCurdy SP, McElroy E, Rauckhorst MR, Tomaras AP, Young JA, Zaniewski RP, Shanmugasundaram V, Han S J Med Chem. 2014 Apr 21. PMID:24694215<ref>PMID:24694215</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 4ool" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Cell division protein 3D structures|Cell division protein 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Pseudomonas aeruginosa PA1R]] | |||
[[Category: Caspers N]] | |||
[[Category: Han S]] | |||
[[Category: Knafels JD]] | |||
Latest revision as of 20:17, 20 September 2023
Crystal structure of PBP3 in complex with compound 14 ((2E)-2-({[(2S)-2-{[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-{[(1,5-dihydroxy-4-oxo-1,4-dihydropyridin-2-yl)methoxy]imino}acetyl]amino}-3-oxopropyl]oxy}imino)pentanedioic acid)
Structural highlights
Publication Abstract from PubMedMultidrug-resistant Gram-negative pathogens are an emerging threat to human health, and addressing this challenge will require development of new antibacterial agents. This can be achieved through an improved molecular understanding of drug-target interactions combined with enhanced delivery of these agents to the site of action. Herein we describe the first application of siderophore receptor-mediated drug uptake of lactivicin analogues as a strategy that enables the development of novel antibacterial agents against clinically relevant Gram-negative bacteria. We report the first crystal structures of several sideromimic conjugated compounds bound to penicillin binding proteins PBP3 and PBP1a from Pseudomonas aeruginosa and characterize the reactivity of lactivicin and beta-lactam core structures. Results from drug sensitivity studies with beta-lactamase enzymes are presented, as well as a structure-based hypothesis to reduce susceptibility to this enzyme class. Finally, mechanistic studies demonstrating that sideromimic modification alters the drug uptake process are discussed. Siderophore Receptor-Mediated Uptake of Lactivicin Analogues in Gram-Negative Bacteria.,Starr J, Brown MF, Aschenbrenner L, Caspers N, Che Y, Gerstenberger BS, Huband M, Knafels JD, Lemmon MM, Li C, McCurdy SP, McElroy E, Rauckhorst MR, Tomaras AP, Young JA, Zaniewski RP, Shanmugasundaram V, Han S J Med Chem. 2014 Apr 21. PMID:24694215[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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