4JXV

X-ray crystal structure of AmpC beta-lactamase from E. coli in complex with a non-covalent inhibitor 3-{[2-(4-CARBOXYPHENYL)ETHYL]SULFAMOYL}THIOPHENE-2-CARBOXYLIC ACID (compound 5)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.76 Å
  • R-Value Free: 0.232 
  • R-Value Work: 0.197 
  • R-Value Observed: 0.199 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Structure-based efforts to optimize a non-beta-lactam inhibitor of AmpC beta-lactamase.

Hendershot, J.M.Mishra, U.J.Smart, R.P.Schroeder, W.Powers, R.A.

(2014) Bioorg Med Chem 22: 3351-3359

  • DOI: https://doi.org/10.1016/j.bmc.2014.04.051
  • Primary Citation of Related Structures:  
    4JXS, 4JXV, 4JXW

  • PubMed Abstract: 

    β-Lactams are the most widely prescribed class of antibiotics, yet their efficacy is threatened by expression of β-lactamase enzymes, which hydrolyze the defining lactam ring of these antibiotics. To overcome resistance due to β-lactamases, inhibitors that do not resemble β-lactams are needed. A novel, non-β-lactam inhibitor for the class C β-lactamase AmpC (3-[(4-chloroanilino)sulfonyl]thiophene-2-carboxylic acid; Ki 26μM) was previously identified. Based on this lead, a series of compounds with the potential to interact with residues at the edge of the active site were synthesized and tested for inhibition of AmpC. The length of the carbon chain spacer was extended by 1, 2, 3, and 4 carbons between the integral thiophene ring and the benzene ring (compounds 4, 5, 6, and 7). Compounds 4 and 6 showed minimal improvement over the lead compound (Ki 18 and 19μM, respectively), and compound 5 inhibited to the same extent as the lead. The X-ray crystal structures of AmpC in complexes with compounds 4, 5, and 6 were determined. The complexes provide insight into the structural reasons for the observed inhibition, and inform future optimization efforts in this series.


  • Organizational Affiliation

    Cell and Molecular Biology Program, Grand Valley State University, Allendale, MI 49401, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Beta-lactamase
A, B
358Escherichia coli K-12Mutation(s): 0 
Gene Names: ampCampAb4150JW4111
EC: 3.5.2.6
UniProt
Find proteins for P00811 (Escherichia coli (strain K12))
Explore P00811 
Go to UniProtKB:  P00811
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP00811
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
1MU Binding MOAD:  4JXV Ki: 3.10e+4 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.76 Å
  • R-Value Free: 0.232 
  • R-Value Work: 0.197 
  • R-Value Observed: 0.199 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 118.656α = 90
b = 77.162β = 115.36
c = 97.651γ = 90
Software Package:
Software NamePurpose
HKL-2000data collection
PHASERphasing
REFMACrefinement
HKL-2000data reduction
HKL-2000data scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2014-04-30
    Type: Initial release
  • Version 1.1: 2014-07-02
    Changes: Database references
  • Version 1.2: 2024-02-28
    Changes: Data collection, Database references, Derived calculations