4GZB

Crystal structure of native AmpC beta-lactamase from Pseudomonas aeruginosa PAO1


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.79 Å
  • R-Value Free: 0.244 
  • R-Value Work: 0.190 
  • R-Value Observed: 0.193 

Starting Model: experimental
View more details

wwPDB Validation   3D Report Full Report


This is version 1.2 of the entry. See complete history


Literature

Structural insight into potent broad-spectrum inhibition with reversible recyclization mechanism: avibactam in complex with CTX-M-15 and Pseudomonas aeruginosa AmpC beta-lactamases

Lahiri, S.D.Mangani, S.Durand-Reville, T.Benvenuti, M.De Luca, F.Sanyal, G.Docquier, J.D.

(2013) Antimicrob Agents Chemother 57: 2496-2505

  • DOI: https://doi.org/10.1128/AAC.02247-12
  • Primary Citation of Related Structures:  
    4GZB, 4HBT, 4HBU, 4HEF

  • PubMed Abstract: 

    Although β-lactams have been the most effective class of antibacterial agents used in clinical practice for the past half century, their effectiveness on Gram-negative bacteria has been eroded due to the emergence and spread of β-lactamase enzymes that are not affected by currently marketed β-lactam/β-lactamase inhibitor combinations. Avibactam is a novel, covalent, non-β-lactam β-lactamase inhibitor presently in clinical development in combination with either ceftaroline or ceftazidime. In vitro studies show that avibactam may restore the broad-spectrum activity of cephalosporins against class A, class C, and some class D β-lactamases. Here we describe the structures of two clinically important β-lactamase enzymes bound to avibactam, the class A CTX-M-15 extended-spectrum β-lactamase and the class C Pseudomonas aeruginosa AmpC β-lactamase, which together provide insight into the binding modes for the respective enzyme classes. The structures reveal similar binding modes in both enzymes and thus provide a rationale for the broad-spectrum inhibitory activity of avibactam. Identification of the key residues surrounding the binding pocket allows for a better understanding of the potency of this scaffold. Finally, avibactam has recently been shown to be a reversible inhibitor, and the structures provide insights into the mechanism of avibactam recyclization. Analysis of the ultra-high-resolution CTX-M-15 structure suggests how the deacylation mechanism favors recyclization over hydrolysis.


  • Organizational Affiliation

    Infection Biosciences, AstraZeneca R&D Boston, Waltham, Massachusetts, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Beta-lactamase371Pseudomonas aeruginosa PAO1Mutation(s): 0 
Gene Names: ampCblaAmpCPA4110
EC: 3.5.2.6
UniProt
Find proteins for P24735 (Pseudomonas aeruginosa (strain ATCC 15692 / DSM 22644 / CIP 104116 / JCM 14847 / LMG 12228 / 1C / PRS 101 / PAO1))
Explore P24735 
Go to UniProtKB:  P24735
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP24735
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
EDO
Query on EDO

Download Ideal Coordinates CCD File 
B [auth A]1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.79 Å
  • R-Value Free: 0.244 
  • R-Value Work: 0.190 
  • R-Value Observed: 0.193 
  • Space Group: P 32 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 83.06α = 90
b = 83.06β = 90
c = 122.42γ = 120
Software Package:
Software NamePurpose
ADSCdata collection
MOLREPphasing
REFMACrefinement
MOSFLMdata reduction
SCALAdata scaling

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2013-04-10
    Type: Initial release
  • Version 1.1: 2014-03-19
    Changes: Database references
  • Version 1.2: 2023-11-08
    Changes: Data collection, Database references, Derived calculations, Refinement description