4Z8D

Antibacterial FabH Inhibitors with Validated Mode of Action in Haemophilus Influenzae by in vitro resistance mutation mapping

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.215 
  • R-Value Work: 0.158 
  • R-Value Observed: 0.161 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history. 


Literature

Antibacterial FabH Inhibitors with Mode of Action Validated in Haemophilus influenzae by in Vitro Resistance Mutation Mapping.

McKinney, D.C., Eyermann, C.J., Gu, R.F., Hu, J., Kazmirski, S.L., Lahiri, S.D., McKenzie, A.R., Shapiro, A.B., Breault, G.

(2016) ACS Infect Dis 2: 456-464

  • DOI: https://doi.org/10.1021/acsinfecdis.6b00053
  • Primary Citation of Related Structures:  
    4Z8D, 5BNM, 5BNR, 5BNS, 5BQS

  • PubMed Abstract: 

    Fatty acid biosynthesis is essential to bacterial growth in Gram-negative pathogens. Several small molecules identified through a combination of high-throughput and fragment screening were cocrystallized with FabH (β-ketoacyl-acyl carrier protein synthase III) from Escherichia coli and Streptococcus pneumoniae. Structure-based drug design was used to merge several scaffolds to provide a new class of inhibitors. After optimization for Gram-negative enzyme inhibitory potency, several compounds demonstrated antimicrobial activity against an efflux-negative strain of Haemophilus influenzae. Mutants resistant to these compounds had mutations in the FabH gene near the catalytic triad, validating FabH as a target for antimicrobial drug discovery.

    • Organizational Affiliation: 

    Infection Innovative Medicines, AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.


Macromolecules
Find similar proteins by: 
(by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
3-oxoacyl-[acyl-carrier-protein] synthase 3
A, B
317Escherichia coli O157:H7Mutation(s): 0 
Gene Names: fabH, Z1730, ECs1469
EC: 2.3.1.180
UniProt
Find proteins for P0A6R0 (Escherichia coli (strain K12))
Explore P0A6R0 
Go to UniProtKB:  P0A6R0
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP0A6R0
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
4LB Binding MOAD:  4Z8D IC50: 6000 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.215 
  • R-Value Work: 0.158 
  • R-Value Observed: 0.161 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 63.37α = 90
b = 79.496β = 90
c = 120.53γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
PDB_EXTRACTdata extraction
SCALAdata scaling
AMoREphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


View more in-depth experimental data
Entry History 

Deposition Data

  • Released Date: 2016-05-04 
    • Deposition Author(s): Lahiri, S.D.

Revision History  (Full details and data files)

  • Version 1.0: 2016-05-04
    Type: Initial release
  • Version 1.1: 2016-09-28
    Changes: Data collection, Database references
  • Version 1.2: 2024-03-06
    Changes: Data collection, Database references, Derived calculations