7RPF

X-ray crystal structure of OXA-24/40 in complex with doripenem


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.205 
  • R-Value Work: 0.172 
  • R-Value Observed: 0.173 

Starting Model: experimental
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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Conformational flexibility in carbapenem hydrolysis drives substrate specificity of the class D carbapenemase OXA-24/40.

Mitchell, J.M.June, C.M.Baggett, V.L.Lowe, B.C.Ruble, J.F.Bonomo, R.A.Leonard, D.A.Powers, R.A.

(2022) J Biol Chem 298: 102127-102127

  • DOI: https://doi.org/10.1016/j.jbc.2022.102127
  • Primary Citation of Related Structures:  
    7RP8, 7RP9, 7RPA, 7RPB, 7RPC, 7RPD, 7RPE, 7RPF, 7RPG

  • PubMed Abstract: 

    The evolution of multidrug resistance in Acinetobacter spp. increases the risk of our best antibiotics losing their efficacy. From a clinical perspective, the carbapenem-hydrolyzing class D β-lactamase subfamily present in Acinetobacter spp. is particularly concerning because of its ability to confer resistance to carbapenems. The kinetic profiles of class D β-lactamases exhibit variability in carbapenem hydrolysis, suggesting functional differences. To better understand the structure-function relationship between the carbapenem-hydrolyzing class D β-lactamase OXA-24/40 found in Acinetobacter baumannii and carbapenem substrates, we analyzed steady-state kinetics with the carbapenem antibiotics meropenem and ertapenem and determined the structures of complexes of OXA-24/40 bound to imipenem, meropenem, doripenem, and ertapenem, as well as the expanded-spectrum cephalosporin cefotaxime, using X-ray crystallography. We show that OXA-24/40 exhibits a preference for ertapenem compared with meropenem, imipenem, and doripenem, with an increase in catalytic efficiency of up to fourfold. We suggest that superposition of the nine OXA-24/40 complexes will better inform future inhibitor design efforts by providing insight into the complicated and varying ways in which carbapenems are selected and bound by class D β-lactamases.


  • Organizational Affiliation

    Department of Chemistry, Grand Valley State University, Allendale, Michigan, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Beta-lactamase245Acinetobacter baumanniiMutation(s): 0 
Gene Names: blaOXA-33bla-OXA-40blaOXA-24blaOXA-40oxa-24oxa40SI89_16690
EC: 3.5.2.6
UniProt
Find proteins for Q8RLA6 (Acinetobacter baumannii)
Explore Q8RLA6 
Go to UniProtKB:  Q8RLA6
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ8RLA6
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
4J6 (Subject of Investigation/LOI)
Query on 4J6

Download Ideal Coordinates CCD File 
C [auth A](4R,5S)-5-[(2S,3R)-3-hydroxy-1-oxobutan-2-yl]-4-methyl-3-({(3S,5S)-5-[(sulfamoylamino)methyl]pyrrolidin-3-yl}sulfanyl)-4,5-dihydro-1H-pyrrole-2-carboxylic acid
C15 H26 N4 O6 S2
QJKQOMNNBOTMCR-PQTSNVLCSA-N
DRW (Subject of Investigation/LOI)
Query on DRW

Download Ideal Coordinates CCD File 
D [auth A](2S,3R,4S)-2-[(2S,3R)-3-hydroxy-1-oxobutan-2-yl]-3-methyl-4-({(3S,5S)-5-[(sulfamoylamino)methyl]pyrrolidin-3-yl}sulfanyl)-3,4-dihydro-2H-pyrrole-5-carboxylic acid
C15 H26 N4 O6 S2
RBKUPZPTQNSPAV-CFINEGTKSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
E [auth A],
F [auth A],
G [auth A]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
BCT
Query on BCT

Download Ideal Coordinates CCD File 
B [auth A]BICARBONATE ION
C H O3
BVKZGUZCCUSVTD-UHFFFAOYSA-M
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
KCX
Query on KCX
A
L-PEPTIDE LINKINGC7 H14 N2 O4LYS
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.205 
  • R-Value Work: 0.172 
  • R-Value Observed: 0.173 
  • Space Group: P 41 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 102.699α = 90
b = 102.699β = 90
c = 84.468γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
SCALEPACKdata scaling
PHASERphasing
PDB_EXTRACTdata extraction
HKL-2000data reduction

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)United StatesR15AI094489-02
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)United StatesR01AI072219

Revision History  (Full details and data files)

  • Version 1.0: 2022-07-06
    Type: Initial release
  • Version 1.1: 2022-07-27
    Changes: Database references
  • Version 1.2: 2023-10-18
    Changes: Data collection, Refinement description
  • Version 1.3: 2023-11-15
    Changes: Data collection