6D1G

Crystal structure of NDM-1 complexed with compound 9


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.15 Å
  • R-Value Free: 0.164 
  • R-Value Work: 0.134 
  • R-Value Observed: 0.135 

wwPDB Validation 3D Report Full Report


This is version 1.3 of the entry. See complete history


Literature

Heteroaryl Phosphonates as Noncovalent Inhibitors of Both Serine- and Metallocarbapenemases.

Pemberton, O.A.Jaishankar, P.Akhtar, A.Adams, J.L.Shaw, L.N.Renslo, A.R.Chen, Y.

(2019) J Med Chem 62: 8480-8496

  • DOI: 10.1021/acs.jmedchem.9b00728
  • Structures With Same Primary Citation

  • PubMed Abstract: 
  • Gram-negative pathogens expressing serine β-lactamases (SBLs) and metallo-β-lactamases (MBLs), especially those with carbapenemase activity, threaten the clinical utility of almost all β-lactam antibiotics. Here we describe the discovery of a heteroa ...

    Gram-negative pathogens expressing serine β-lactamases (SBLs) and metallo-β-lactamases (MBLs), especially those with carbapenemase activity, threaten the clinical utility of almost all β-lactam antibiotics. Here we describe the discovery of a heteroaryl phosphonate scaffold that exhibits noncovalent cross-class inhibition of representative carbapenemases, specifically the SBL KPC-2 and the MBLs NDM-1 and VIM-2. The most potent lead, compound 16 , exhibited low nM to low μM inhibition of KPC-2, NDM-1, and VIM-2. Compound 16 potentiated imipenem efficacy against resistant clinical and laboratory bacterial strains expressing carbapenemases while showing some cytotoxicity toward human HEK293T cells only at concentrations above 100 μg/mL. Complex structures with KPC-2, NDM-1, and VIM-2 demonstrate how these inhibitors achieve high binding affinity to both enzyme classes. These findings provide a structurally and mechanistically new scaffold for drug discovery targeting multidrug resistant Gram-negative pathogens and more generally highlight the active site features of carbapenemases that can be leveraged for lead discovery.


    Organizational Affiliation

    Department of Molecular Medicine , University of South Florida Morsani College of Medicine , 12901 Bruce B. Downs Boulevard, MDC 3522 , Tampa , Florida 33612 , United States.



Macromolecules

Find similar proteins by: Sequence  |  Structure

Entity ID: 1
MoleculeChainsSequence LengthOrganismDetails
Metallo-beta-lactamase type 2
A
233Klebsiella pneumoniaeMutation(s): 0 
Gene Names: blaNDM-1
EC: 3.5.2.6
Find proteins for C7C422 (Klebsiella pneumoniae)
Go to UniProtKB:  C7C422
Small Molecules
Ligands 3 Unique
IDChainsName / Formula / InChI Key2D Diagram3D Interactions
YKG
Query on YKG

Download CCD File 
A
[(5-bromo-7-methyl-2-oxo-2H-1-benzopyran-4-yl)methyl]phosphonic acid
C11 H10 Br O5 P
AVDUOTYJUPESMO-UHFFFAOYSA-N
 Ligand Interaction
ZN
Query on ZN

Download CCD File 
A
ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
 Ligand Interaction
ACT
Query on ACT

Download CCD File 
A
ACETATE ION
C2 H3 O2
QTBSBXVTEAMEQO-UHFFFAOYSA-M
 Ligand Interaction
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.15 Å
  • R-Value Free: 0.164 
  • R-Value Work: 0.134 
  • R-Value Observed: 0.135 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 41.5α = 90
b = 60.15β = 98.1
c = 41.85γ = 90
Software Package:
Software NamePurpose
iMOSFLMdata reduction
SCALAdata scaling
PHASERphasing
PHENIXrefinement
PDB_EXTRACTdata extraction

Structure Validation

View Full Validation Report



Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)United StatesR01AI103158-04

Revision History 

  • Version 1.0: 2019-04-17
    Type: Initial release
  • Version 1.1: 2019-10-02
    Changes: Data collection, Database references
  • Version 1.2: 2019-10-09
    Changes: Data collection, Database references
  • Version 1.3: 2019-12-18
    Changes: Author supporting evidence