4bku: Difference between revisions
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<StructureSection load='4bku' size='340' side='right'caption='[[4bku]], [[Resolution|resolution]] 1.84Å' scene=''> | <StructureSection load='4bku' size='340' side='right'caption='[[4bku]], [[Resolution|resolution]] 1.84Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4bku]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4BKU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4BKU FirstGlance]. <br> | <table><tr><td colspan='2'>[[4bku]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Burkholderia_pseudomallei_1026b Burkholderia pseudomallei 1026b]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4BKU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4BKU FirstGlance]. <br> | ||
</td></tr><tr id=' | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.841Å</td></tr> | ||
<tr id=' | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1S5:5-(4-AMINO-2-METHYLPHENOXY)-2-HEXYL-4-HYDROXY-1-METHYLPYRIDINIUM'>1S5</scene>, <scene name='pdbligand=NAI:1,4-DIHYDRONICOTINAMIDE+ADENINE+DINUCLEOTIDE'>NAI</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=4bku FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bku OCA], [https://pdbe.org/4bku PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4bku RCSB], [https://www.ebi.ac.uk/pdbsum/4bku PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4bku 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=4bku FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bku OCA], [https://pdbe.org/4bku PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4bku RCSB], [https://www.ebi.ac.uk/pdbsum/4bku PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4bku ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | |||
[https://www.uniprot.org/uniprot/A0A0H3HP34_BURP2 A0A0H3HP34_BURP2] | |||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
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__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Burkholderia pseudomallei 1026b]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Hirschbeck | [[Category: Hirschbeck MW]] | ||
[[Category: Kisker | [[Category: Kisker C]] | ||
[[Category: Liu | [[Category: Liu N]] | ||
[[Category: Neckles | [[Category: Neckles C]] | ||
[[Category: Tonge | [[Category: Tonge PJ]] | ||
Latest revision as of 14:53, 20 December 2023
Enoyl-ACP reductase FabI from Burkholderia pseudomallei with cofactor NADH and inhibitor PT155Enoyl-ACP reductase FabI from Burkholderia pseudomallei with cofactor NADH and inhibitor PT155
Structural highlights
FunctionPublication Abstract from PubMedDetermining the molecular basis for target selectivity is of particular importance in drug discovery. The ideal antibiotic should be active against a broad spectrum of pathogenic organisms with a minimal effect on human targets. CG400549 - a Staphylococcus-specific 2-pyridone compound that inhibits the enoyl-ACP reductase (FabI) - has recently been shown to possess human efficacy for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections (www.crystalgenomics.com), which constitute a serious threat to human health. In this study, we solved the structures of three different FabI homologues in complex with several pyridone inhibitors including CG400549. Based on these structures we rationalize the 65-fold reduced affinity of CG400549 towards Escherichia coli vs. S. aureus FabI and implement concepts to improve the spectrum of antibacterial activity. The identification of different conformational states along the reaction coordinate of the enzymatic hydride transfer provides an elegant visual depiction of the relationship between catalysis and inhibition, which facilitates rational inhibitor design. Ultimately, we developed the novel 4-pyridone-based FabI inhibitor PT166 that retained favorable pharmacokinetics and efficacy in a mouse model of S. aureus infection with extended activity against Gram-negative and mycobacterial organisms. Rational Design of Broad-Spectrum Antibacterial Activity based on a Clinically Relevant Enoyl-ACP Reductase Inhibitor.,Schiebel J, Chang A, Shah S, Lu Y, Liu L, Pan P, Hirschbeck MW, Tareilus M, Eltschkner S, Yu W, Cummings JE, Knudson SE, Bommineni GR, Walker SG, Slayden RA, Sotriffer CA, Tonge PJ, Kisker C J Biol Chem. 2014 Apr 16. PMID:24739388[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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