6QW7

Crystal structure of L2 complexed with relebactam (16 hour soak)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.78 Å
  • R-Value Free: 0.205 
  • R-Value Work: 0.159 
  • R-Value Observed: 0.162 

Starting Model: experimental
View more details

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 

Created with Raphaël 2.3.0Worse 01 BetterLigand structure goodness of fit to experimental dataBest fitted MK7Click on this verticalbar to view details

This is version 1.3 of the entry. See complete history


Literature

Molecular Basis of Class A beta-Lactamase Inhibition by Relebactam.

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

(2019) Antimicrob Agents Chemother 63

  • DOI: https://doi.org/10.1128/AAC.00564-19
  • Primary Citation of Related Structures:  
    6QW7, 6QW8, 6QW9, 6QWA, 6QWB, 6QWC, 6QWD, 6QWE

  • PubMed Abstract: 

    β-Lactamase production is the major β-lactam resistance mechanism in Gram-negative bacteria. β-Lactamase inhibitors (BLIs) efficacious against serine β-lactamase (SBL) producers, especially strains carrying the widely disseminated class A enzymes, are required. Relebactam, a diazabicyclooctane (DBO) BLI, is in phase 3 clinical trials in combination with imipenem for the treatment of infections by multidrug-resistant Enterobacteriaceae We show that relebactam inhibits five clinically important class A SBLs (despite their differing spectra of activity), representing both chromosomal and plasmid-borne enzymes, i.e., the extended-spectrum β-lactamases L2 (inhibition constant 3 μM) and CTX-M-15 (21 μM) and the carbapenemases KPC-2, -3, and -4 (1 to 5 μM). Against purified class A SBLs, relebactam is an inferior inhibitor compared with the clinically approved DBO avibactam (9- to 120-fold differences in half maximal inhibitory concentration [IC 50 ]). MIC assays indicate relebactam potentiates β-lactam (imipenem) activity against KPC-producing Klebsiella pneumoniae , with similar potency to avibactam (with ceftazidime). Relebactam is less effective than avibactam in combination with aztreonam against Stenotrophomonas maltophilia K279a. X-ray crystal structures of relebactam bound to CTX-M-15, L2, KPC-2, KPC-3, and KPC-4 reveal its C2-linked piperidine ring can sterically clash with Asn104 (CTX-M-15) or His/Trp105 (L2 and KPCs), rationalizing its poorer inhibition activity than that of avibactam, which has a smaller C2 carboxyamide group. Mass spectrometry and crystallographic data show slow, pH-dependent relebactam desulfation by KPC-2, -3, and -4. This comprehensive comparison of relebactam binding across five clinically important class A SBLs will inform the design of future DBOs, with the aim of improving clinical efficacy of BLI-β-lactam combinations.


  • Organizational Affiliation

    School of Cellular and Molecular Medicine, Biomedical Sciences Building, University of Bristol, Bristol, United Kingdom.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Beta-lactamase
A, B
278Stenotrophomonas maltophiliaMutation(s): 0 
Gene Names: blaL2L2
EC: 3.5.2.6
UniProt
Find proteins for Q9RBQ1 (Stenotrophomonas maltophilia)
Explore Q9RBQ1 
Go to UniProtKB:  Q9RBQ1
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ9RBQ1
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
MK7 (Subject of Investigation/LOI)
Query on MK7

Download Ideal Coordinates CCD File 
D [auth B](2S,5R)-1-formyl-N-(piperidin-4-yl)-5-[(sulfooxy)amino]piperidine-2-carboxamide
C12 H22 N4 O6 S
VGHMECNLFQGIJM-MNOVXSKESA-N
DSN
Query on DSN

Download Ideal Coordinates CCD File 
C [auth A]D-SERINE
C3 H7 N O3
MTCFGRXMJLQNBG-UWTATZPHSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.78 Å
  • R-Value Free: 0.205 
  • R-Value Work: 0.159 
  • R-Value Observed: 0.162 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 69.958α = 90
b = 84.34β = 90
c = 94.136γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
xia2data reduction
Aimlessdata scaling
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 

Created with Raphaël 2.3.0Worse 01 BetterLigand structure goodness of fit to experimental dataBest fitted MK7Click on this verticalbar to view details

Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
Biotechnology and Biological Sciences Research CouncilUnited KingdomBB/J014400/1

Revision History  (Full details and data files)

  • Version 1.0: 2019-08-21
    Type: Initial release
  • Version 1.1: 2019-10-02
    Changes: Data collection, Database references
  • Version 1.2: 2024-01-24
    Changes: Data collection, Database references, Refinement description
  • Version 1.3: 2024-10-16
    Changes: Structure summary