6TD1

Crystal structure of VNRX-5133 (taniborbactam) bound to KPC-2


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.20 Å
  • R-Value Free: 0.152 
  • R-Value Work: 0.136 
  • R-Value Observed: 0.137 

Starting Model: experimental
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This is version 1.4 of the entry. See complete history


Literature

Cyclic boronates as versatile scaffolds for KPC-2 beta-lactamase inhibition.

Tooke, C.L.Hinchliffe, P.Krajnc, A.Mulholland, A.J.Brem, J.Schofield, C.J.Spencer, J.

(2020) RSC Med Chem 11: 491-496

  • DOI: https://doi.org/10.1039/c9md00557a
  • Primary Citation of Related Structures:  
    6TD0, 6TD1

  • PubMed Abstract: 

    Klebsiella pneumoniae carbapenemase-2 (KPC-2) is a serine-β-lactamase (SBL) capable of hydrolysing almost all β-lactam antibiotics. We compare KPC-2 inhibition by vaborbactam, a clinically-approved monocyclic boronate, and VNRX-5133 (taniborbactam), a bicyclic boronate in late-stage clinical development. Vaborbactam inhibition is slowly reversible, whereas taniborbactam has an off-rate indicating essentially irreversible complex formation and a 15-fold higher on-rate, although both potentiate β-lactam activity against KPC-2-expressing K. pneumoniae . High resolution X-ray crystal structures reveal closely related binding modes for both inhibitors to KPC-2, with differences apparent only in positioning of the endocyclic boronate ester oxygen. The results indicate the bicyclic boronate scaffold as both an efficient, long-lasting, KPC-2 inhibitor and capable of supporting further iterations that may improve potency against specific enzyme targets and pre-empt the emergence of inhibitor resistant KPC-2 variants.


  • Organizational Affiliation

    School of Cellular and Molecular Medicine , Biomedical Sciences Building , University of Bristol , Bristol , BS8 1TD , UK . Email: [email protected].


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Carbapenem-hydrolyzing beta-lactamase KPC290Klebsiella pneumoniaeMutation(s): 0 
Gene Names: blakpckpc1
EC: 3.5.2.6
UniProt
Find proteins for Q9F663 (Klebsiella pneumoniae)
Explore Q9F663 
Go to UniProtKB:  Q9F663
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ9F663
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.20 Å
  • R-Value Free: 0.152 
  • R-Value Work: 0.136 
  • R-Value Observed: 0.137 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 60.557α = 90
b = 79.761β = 90
c = 56.021γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2020-01-22
    Type: Initial release
  • Version 1.1: 2020-03-25
    Changes: Database references
  • Version 1.2: 2021-02-03
    Changes: Database references
  • Version 1.3: 2024-01-24
    Changes: Data collection, Database references, Refinement description
  • Version 1.4: 2024-10-23
    Changes: Structure summary