4is9: Difference between revisions

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== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[4is9]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli_IHE3034 Escherichia coli IHE3034]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4IS9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4IS9 FirstGlance]. <br>
<table><tr><td colspan='2'>[[4is9]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli_IHE3034 Escherichia coli IHE3034]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4IS9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4IS9 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=IPA:ISOPROPYL+ALCOHOL'>IPA</scene>, <scene name='pdbligand=LTF:(4R)-2-(3,4-DIMETHOXY-5-PROPYLPHENYL)-N-HYDROXY-4,5-DIHYDRO-1,3-OXAZOLE-4-CARBOXAMIDE'>LTF</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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]] 2.13&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=IPA:ISOPROPYL+ALCOHOL'>IPA</scene>, <scene name='pdbligand=LTF:(4R)-2-(3,4-DIMETHOXY-5-PROPYLPHENYL)-N-HYDROXY-4,5-DIHYDRO-1,3-OXAZOLE-4-CARBOXAMIDE'>LTF</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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=4is9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4is9 OCA], [https://pdbe.org/4is9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4is9 RCSB], [https://www.ebi.ac.uk/pdbsum/4is9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4is9 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=4is9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4is9 OCA], [https://pdbe.org/4is9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4is9 RCSB], [https://www.ebi.ac.uk/pdbsum/4is9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4is9 ProSAT]</span></td></tr>
</table>
</table>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The LpxC enzyme in the lipid A biosynthetic pathway is one of the most promising and clinically unexploited antibiotic targets for treatment of multidrug-resistant Gram-negative infections. Progress in medicinal chemistry has led to the discovery of potent LpxC inhibitors with a variety of chemical scaffolds and distinct antibiotic profiles. The vast majority of these compounds, including the nanomolar inhibitors L-161,240 and BB-78485, are highly effective in suppressing the activity of E. coli LpxC (EcLpxC), but not divergent orthologs such as P. aeruginosa LpxC (PaLpxC) in vitro. The molecular basis for such promiscuous inhibition of EcLpxC has remained poorly understood. Here, we report the crystal structure of EcLpxC bound to L-161,240, providing the first molecular insight into L-161,240 inhibition. Additionally, structural analysis of the EcLpxC/L-161,240 complex together with the EcLpxC/BB-78485 complex reveals an unexpected backbone flipping of the Insert I betaa-betab loop in EcLpxC in comparison with previously reported crystal structures of EcLpxC complexes with L-threonyl-hydroxamate-based broad-spectrum inhibitors. Such a conformational switch, which has only been observed in EcLpxC, but not in divergent orthologs such as PaLpxC, results in expansion of the active site of EcLpxC, enabling it to accommodate LpxC inhibitors with a variety of head groups, including compounds containing single (R- or S- enantiomers) or double substitutions at the neighboring Calpha atom of the hydroxamate warhead group. These results highlight the importance of understanding inherent conformational plasticity of target proteins in lead optimization.
Structural Basis of the Promiscuous Inhibitor Susceptibility of E. coli LpxC.,Lee CJ, Liang X, Gopalaswamy R, Najeeb J, Ark ED, Toone EJ, Zhou P ACS Chem Biol. 2013 Oct 11. PMID:24117400<ref>PMID:24117400</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4is9" style="background-color:#fffaf0;"></div>


==See Also==
==See Also==
*[[UDP-3-O-acyl-N-acetylglucosamine deacetylase|UDP-3-O-acyl-N-acetylglucosamine deacetylase]]
*[[UDP-3-O-acyl-N-acetylglucosamine deacetylase|UDP-3-O-acyl-N-acetylglucosamine deacetylase]]
== References ==
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>

Latest revision as of 14:59, 1 March 2024

Crystal Structure of the Escherichia coli LpxC/L-161,240 complexCrystal Structure of the Escherichia coli LpxC/L-161,240 complex

Structural highlights

4is9 is a 2 chain structure with sequence from Escherichia coli IHE3034. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.13Å
Ligands:, , ,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

See Also

4is9, resolution 2.13Å

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