View source for 4cv1


==Crystal structure of S. aureus FabI in complex with NADPH and CG400549==
<StructureSection load='4cv1' size='340' side='right'caption='[[4cv1]], [[Resolution|resolution]] 1.95&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4cv1]] is a 8 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli_BL21(DE3) Escherichia coli BL21(DE3)]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4CV1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4CV1 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]] 1.95&#8491;</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=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=4cv1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4cv1 OCA], [https://pdbe.org/4cv1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4cv1 RCSB], [https://www.ebi.ac.uk/pdbsum/4cv1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4cv1 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&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4cv1" style="background-color:#fffaf0;"></div>

==See Also==
*[[Enoyl-Acyl-Carrier Protein Reductase 3D structures|Enoyl-Acyl-Carrier Protein Reductase 3D structures]]
== References ==
<references/>
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</StructureSection>
[[Category: Large Structures]]
[[Category: Chang A]]
[[Category: Kisker C]]
[[Category: Schiebel J]]
[[Category: Shah S]]
[[Category: Tonge PJ]]