6P89

E.coli LpxD in complex with compound 7


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.40 Å
  • R-Value Free: 0.188 
  • R-Value Work: 0.167 
  • R-Value Observed: 0.168 

wwPDB Validation   3D Report Full Report

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This is version 1.2 of the entry. See complete history


Literature

Structural and Biological Basis of Small Molecule Inhibition ofEscherichia coliLpxD Acyltransferase Essential for Lipopolysaccharide Biosynthesis.

Ma, 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.

(2020) ACS Infect Dis 6: 1480-1489

  • DOI: https://doi.org/10.1021/acsinfecdis.9b00127
  • Primary Citation of Related Structures:  
    6P83, 6P84, 6P85, 6P86, 6P87, 6P88, 6P89, 6P8A, 6P8B

  • PubMed Abstract: 

    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 LpxD Gly268Cys 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.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
UDP-3-O-(3-hydroxymyristoyl)glucosamine N-acyltransferase
A, B, C
343Escherichia coliMutation(s): 0 
Gene Names: 
lpxDlpxD_1lpxD_2A8C65_17800A9R57_04450AC789_1c01770ACN002_0184ACN77_17005ACN81_28485ACU57_18525ACU90_26495AM270_18210AML07_22885AML35_22825APZ14_11060AUQ13_07450AUS26_23195AW059_09890AW106_08805B1K96_12940B7C53_01310BANRA_00558BANRA_00653BANRA_02262BANRA_03350BET08_19125BHF46_07835BHS81_00700BHS87_00855BIZ41_19025BJJ90_21310BK292_13720BK400_03560BMT53_09465BN17_46021BTQ06_06540BUE81_01655BVL39_02135BW690_02415BZL31_14885C2U48_09555C4J69_03380C5N07_08630C5P01_08975C5P43_07335C6669_04195C6986_01145C7235_20180C7B06_05915C7B07_04225CA593_02815CG691_14440CG692_09445CG705_12975CG706_12690COD30_14715COD46_06685CR538_20590CR539_04985CRM83_15040CXB56_23080D0X26_09365D2184_08545D2185_20180D2F89_01460D3821_06260D3O91_03240D3Y67_16455D9D20_18680D9D55_03030D9D69_06830D9E22_13300D9E35_14480D9G42_07535D9H66_18155D9H68_13825D9I18_15010D9I87_01590D9I97_03755D9J11_16875D9J44_14030DIV22_06320DL545_20340DMZ31_06810DNQ41_04690DNQ45_10065DQF57_05615DQO13_06200DS732_05825DTL43_05870EAI42_08350EAI46_03595EAI52_11055EC1094V2_3672EC3234A_2c01610EC3426_00931EC382_03005ECTO6_03883ED287_04550ED600_04595EEP23_00115EFV01_09910EFV02_20465EFV04_15215EFV08_17150EFV11_08135EFV12_18845EFV15_17225EFV17_09875EIA13_13600EL75_3585EL79_3695EL80_3642ERS085374_03841ERS150873_01122ERS150876_00054FORC28_5013HW43_04650JD73_13090NCTC10429_04183NCTC10865_05054NCTC11022_04906NCTC11126_03647NCTC13462_02218NCTC8500_04533NCTC8960_01551NCTC9037_04178NCTC9045_04699NCTC9055_00956NCTC9058_02808NCTC9062_04225NCTC9706_01326NCTC9969_04255PU06_22990RG28_03860RK56_027945RX35_04913SAMEA3472043_02537SAMEA3472044_04146SAMEA3472047_02509SAMEA3472070_02384SAMEA3472080_03763SAMEA3472114_03609SAMEA3484427_01386SAMEA3484429_01095SAMEA3752553_02884SAMEA3752557_00885SAMEA3752559_03701SAMEA3753064_03381SAMEA3753097_03916SAMEA3753290_00404SAMEA3753300_01852SK85_00179WQ89_09605WR15_02380

EC: 2.3.1.191
UniProt
Find proteins for P21645 (Escherichia coli (strain K12))
Explore P21645 
Go to UniProtKB:  P21645
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP21645
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.40 Å
  • R-Value Free: 0.188 
  • R-Value Work: 0.167 
  • R-Value Observed: 0.168 
  • Space Group: P 32 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 96.793α = 90
b = 96.793β = 90
c = 216.305γ = 120
Software Package:
Software NamePurpose
SCALAdata scaling
PHENIXrefinement
PDB_EXTRACTdata extraction
XDSdata reduction
PHASERphasing

Structure Validation

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Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2019-08-28
    Type: Initial release
  • Version 1.1: 2020-06-24
    Changes: Database references
  • Version 1.2: 2023-10-11
    Changes: Data collection, Database references, Derived calculations, Refinement description