Loading
PDBj
MenuPDBj@FacebookPDBj@X(formerly Twitter)PDBj@BlueSkyPDBj@YouTubewwPDB FoundationwwPDB
RCSB PDBPDBeBMRBAdv. SearchSearch help

6P83

E.coli LpxD in complex with compound 1o

Summary for 6P83
Entry DOI10.2210/pdb6p83/pdb
DescriptorUDP-3-O-(3-hydroxymyristoyl)glucosamine N-acyltransferase, MAGNESIUM ION, 4-(2-chlorophenyl)-3-hydroxy-7,7-dimethyl-2-phenyl-2,6,7,8-tetrahydro-5H-pyrazolo[3,4-b]quinolin-5-one, ... (4 entities in total)
Functional Keywordslps synthesis, transferase, transferase-inhibitor complex, transferase/inhibitor
Biological sourceEscherichia coli
Total number of polymer chains3
Total formula weight109606.19
Authors
Ma, X.,Shia, S. (deposition date: 2019-06-06, release date: 2019-08-28, Last modification date: 2023-10-11)
Primary citationMa, X.,Prathapam, R.,Wartchow, C.,Chie-Leon, B.,Ho, C.M.,De Vicente, J.,Han, W.,Li, M.,Lu, Y.,Ramurthy, S.,Shia, S.,Steffek, M.,Uehara, T.
Structural and Biological Basis of Small Molecule Inhibition ofEscherichia coliLpxD Acyltransferase Essential for Lipopolysaccharide Biosynthesis.
Acs Infect Dis., 6:1480-1489, 2020
Cited by
PubMed Abstract: LpxD, acyl-ACP-dependent -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 ), that inhibit the enzymatic activity of () LpxD. Here, we use these inhibitors to chemically validate LpxD as an attractive antibacterial target. We first found that compound was oxidized in solution to the more stable aromatized tetrahydro-pyrazolo-quinolinone compound . From the strain deficient in efflux, we isolated a mutant that was less susceptible to compound and had an missense mutation (Gly268Cys), supporting the cellular on-target activity. Using surface plasma resonance, we showed direct binding to LpxD for compound and other reported LpxD inhibitors . Furthermore, we determined eight cocrystal structures of 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 costructure rationalized the reduced activity of compound in the LpxD 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.
PubMed: 31402665
DOI: 10.1021/acsinfecdis.9b00127
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (1.7 Å)
Structure validation

227344

數據於2024-11-13公開中

PDB statisticsPDBj update infoContact PDBjnumon