6p8b: Difference between revisions
Jump to navigation
Jump to search
New page: '''Unreleased structure''' The entry 6p8b is ON HOLD Authors: Description: Category: Unreleased Structures |
No edit summary |
||
| (3 intermediate revisions by the same user not shown) | |||
| Line 1: | Line 1: | ||
==E.coli LpxD in complex with peptide FITC-RJPXD33== | |||
<StructureSection load='6p8b' size='340' side='right'caption='[[6p8b]], [[Resolution|resolution]] 2.00Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6p8b]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli] and [https://en.wikipedia.org/wiki/Phage_display_vector_pdvec0 Phage display vector pdvec0]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6P8B OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6P8B 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]] 2Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=O3V:3-hydroxy-7,7-dimethyl-2-phenyl-4-(thiophen-2-yl)-2,6,7,8-tetrahydro-5H-pyrazolo[3,4-b]quinolin-5-one'>O3V</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=6p8b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6p8b OCA], [https://pdbe.org/6p8b PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6p8b RCSB], [https://www.ebi.ac.uk/pdbsum/6p8b PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6p8b ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/LPXD_ECOLI LPXD_ECOLI] Catalyzes the N-acylation of UDP-3-O-(hydroxymyristoyl)glucosamine using 3-hydroxymyristoyl-ACP as the acyl donor. Is involved in the biosynthesis of lipid A, a phosphorylated glycolipid that anchors the lipopolysaccharide to the outer membrane of the cell. Prefers R-3-hydroxymyristoyl-ACP over R-3-hydroxypalmitoyl-ACP as the acyl donor in vitro, which is consistent with the structure of E.coli lipid A that contains over 95% (R)-3-hydroxymyristate at the 2 and 2' positions.<ref>PMID:8444173</ref> <ref>PMID:19655786</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
LpxD, acyl-ACP-dependent N-acyltransferase, is the third enzyme of lipid A biosynthesis in Gram-negative bacteria. A recent probe-based screen identified several compounds, including 6359-0284 (compound 1), that inhibit the enzymatic activity of Escherichia coli (E. coli) LpxD. Here, we use these inhibitors to chemically validate LpxD as an attractive antibacterial target. We first found that compound 1 was oxidized in solution to the more stable aromatized tetrahydro-pyrazolo-quinolinone compound 1o. From the Escherichia coli strain deficient in efflux, we isolated a mutant that was less susceptible to compound 1o and had an lpxD missense mutation (Gly268Cys), supporting the cellular on-target activity. Using surface plasma resonance, we showed direct binding to E. coli LpxD for compound 1o and other reported LpxD inhibitors in vitro. Furthermore, we determined eight cocrystal structures of E. coli LpxD/inhibitor complexes. These costructures pinpointed the 4'-phosphopantetheine binding site as the common ligand binding hotspot, where hydrogen bonds to Gly269 and/or Gly287 were important for inhibitor binding. In addition, the LpxD/compound 1o costructure rationalized the reduced activity of compound 1o in the LpxDGly268Cys mutant. Moreover, we obtained the LpxD structure in complex with a previously reported LpxA/LpxD dual targeting peptide inhibitor, RJPXD33, providing structural rationale for the unique dual targeting properties of this peptide. Given that the active site residues of LpxD are conserved in multidrug resistant Enterobacteriaceae, this work paves the way for future LpxD drug discovery efforts combating these Gram-negative pathogens. | |||
Structural and Biological Basis of Small Molecule Inhibition of Escherichia coli LpxD Acyltransferase Essential for Lipopolysaccharide Biosynthesis.,Ma X, Prathapam R, Wartchow C, Chie-Leon B, Ho CM, De Vicente J, Han W, Li M, Lu Y, Ramurthy S, Shia S, Steffek M, Uehara T ACS Infect Dis. 2019 Aug 22. doi: 10.1021/acsinfecdis.9b00127. PMID:31402665<ref>PMID:31402665</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 6p8b" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[UDP-3-O-(3-hydroxymyristoyl)glucosamine N-acyltransferase|UDP-3-O-(3-hydroxymyristoyl)glucosamine N-acyltransferase]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Escherichia coli]] | |||
[[Category: Large Structures]] | |||
[[Category: Phage display vector pdvec0]] | |||
[[Category: Ma X]] | |||
[[Category: Shia S]] | |||