4mqy: Difference between revisions

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== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[4mqy]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4MQY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4MQY FirstGlance]. <br>
<table><tr><td colspan='2'>[[4mqy]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4MQY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4MQY FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2CW:4-[4-(4-AMINOPHENYL)BUTA-1,3-DIYN-1-YL]-N-[(2S,3R)-3-HYDROXY-2-METHYL-1-NITROSO-1-OXOBUTAN-2-YL]BENZAMIDE'>2CW</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=UKW:4-ETHYNYL-N-[(1S,2R)-2-HYDROXY-1-(OXOCARBAMOYL)PROPYL]BENZAMIDE'>UKW</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]] 2.005&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2CW:4-[4-(4-AMINOPHENYL)BUTA-1,3-DIYN-1-YL]-N-[(2S,3R)-3-HYDROXY-2-METHYL-1-NITROSO-1-OXOBUTAN-2-YL]BENZAMIDE'>2CW</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=UKW:4-ETHYNYL-N-[(1S,2R)-2-HYDROXY-1-(OXOCARBAMOYL)PROPYL]BENZAMIDE'>UKW</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=4mqy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4mqy OCA], [https://pdbe.org/4mqy PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4mqy RCSB], [https://www.ebi.ac.uk/pdbsum/4mqy PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4mqy 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=4mqy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4mqy OCA], [https://pdbe.org/4mqy PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4mqy RCSB], [https://www.ebi.ac.uk/pdbsum/4mqy PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4mqy ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
[https://www.uniprot.org/uniprot/LPXC_ECOLI LPXC_ECOLI] Catalyzes the hydrolysis of UDP-3-O-myristoyl-N-acetylglucosamine to form UDP-3-O-myristoylglucosamine and acetate, the committed step in lipid A biosynthesis.[HAMAP-Rule:MF_00388]<ref>PMID:10026271</ref> <ref>PMID:8530464</ref> <ref>PMID:8824222</ref> <ref>PMID:18289052</ref>  
[https://www.uniprot.org/uniprot/LPXC_ECOLI LPXC_ECOLI] Catalyzes the hydrolysis of UDP-3-O-myristoyl-N-acetylglucosamine to form UDP-3-O-myristoylglucosamine and acetate, the committed step in lipid A biosynthesis.[HAMAP-Rule:MF_00388]<ref>PMID:10026271</ref> <ref>PMID:8530464</ref> <ref>PMID:8824222</ref> <ref>PMID:18289052</ref>  
<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 4mqy" style="background-color:#fffaf0;"></div>


==See Also==
==See Also==

Latest revision as of 15:28, 1 March 2024

Crystal Structure of the Escherichia coli LpxC/LPC-138 complexCrystal Structure of the Escherichia coli LpxC/LPC-138 complex

Structural highlights

4mqy is a 1 chain structure with sequence from Escherichia coli. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.005Å
Ligands:, , , ,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

LPXC_ECOLI Catalyzes the hydrolysis of UDP-3-O-myristoyl-N-acetylglucosamine to form UDP-3-O-myristoylglucosamine and acetate, the committed step in lipid A biosynthesis.[HAMAP-Rule:MF_00388][1] [2] [3] [4]

See Also

References

  1. ↑ Jackman JE, Raetz CR, Fierke CA. UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase of Escherichia coli is a zinc metalloenzyme. Biochemistry. 1999 Feb 9;38(6):1902-11. doi: 10.1021/bi982339s. PMID:10026271 doi:http://dx.doi.org/10.1021/bi982339s
  2. ↑ Young K, Silver LL, Bramhill D, Cameron P, Eveland SS, Raetz CR, Hyland SA, Anderson MS. The envA permeability/cell division gene of Escherichia coli encodes the second enzyme of lipid A biosynthesis. UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase. J Biol Chem. 1995 Dec 22;270(51):30384-91. doi: 10.1074/jbc.270.51.30384. PMID:8530464 doi:http://dx.doi.org/10.1074/jbc.270.51.30384
  3. ↑ Sorensen PG, Lutkenhaus J, Young K, Eveland SS, Anderson MS, Raetz CR. Regulation of UDP-3-O-[R-3-hydroxymyristoyl]-N-acetylglucosamine deacetylase in Escherichia coli. The second enzymatic step of lipid a biosynthesis. J Biol Chem. 1996 Oct 18;271(42):25898-905. doi: 10.1074/jbc.271.42.25898. PMID:8824222 doi:http://dx.doi.org/10.1074/jbc.271.42.25898
  4. ↑ Barb AW, Zhou P. Mechanism and inhibition of LpxC: an essential zinc-dependent deacetylase of bacterial lipid A synthesis. Curr Pharm Biotechnol. 2008 Feb;9(1):9-15. PMID:18289052

4mqy, resolution 2.00Å

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