4cv0: Difference between revisions
New page: '''Unreleased structure''' The entry 4cv0 is ON HOLD Authors: Schiebel, J., Chang, A., Shah, S., Tonge, P.J., Kisker, C. Description: Crystal structure of S. aureus FabI in complex wit... |
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==Crystal structure of S. aureus FabI in complex with NADPH and CG400549 (small unit cell)== | |||
<StructureSection load='4cv0' size='340' side='right'caption='[[4cv0]], [[Resolution|resolution]] 2.20Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4cv0]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Staphylococcus_aureus Staphylococcus aureus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4CV0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4CV0 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]] 2.2Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene>, <scene name='pdbligand=PT6:1-(3-AMINO-2-METHYLBENZYL)-4-[2-(THIOPHEN-2-YL)ETHOXY]PYRIDIN-2(1H)-ONE'>PT6</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=4cv0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4cv0 OCA], [https://pdbe.org/4cv0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4cv0 RCSB], [https://www.ebi.ac.uk/pdbsum/4cv0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4cv0 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/A0A0H3JLH9_STAAN A0A0H3JLH9_STAAN] | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Determining 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<ref>PMID:24739388</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 4cv0" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Enoyl-Acyl-Carrier Protein Reductase 3D structures|Enoyl-Acyl-Carrier Protein Reductase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Staphylococcus aureus]] | |||
[[Category: Chang A]] | |||
[[Category: Kisker C]] | |||
[[Category: Schiebel J]] | |||
[[Category: Shah S]] | |||
[[Category: Tonge PJ]] | |||
Latest revision as of 15:16, 20 December 2023
Crystal structure of S. aureus FabI in complex with NADPH and CG400549 (small unit cell)Crystal structure of S. aureus FabI in complex with NADPH and CG400549 (small unit cell)
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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