1ONG

SHV-1 beta-lactamase with a penem inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.10 Å
  • R-Value Free: 0.186 
  • R-Value Work: 0.141 
  • R-Value Observed: 0.141 

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Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Inhibition of Class A and Class C Beta-Lactamases by Penems: Crystallographic Structures of a Novel 1,4-Thiazepine Intermediate

Nukaga, M.Abe, T.Venkatesan, A.M.Mansour, T.S.Bonomo, R.A.Knox, J.R.

(2003) Biochemistry 42: 13152-13159

  • DOI: https://doi.org/10.1021/bi034986b
  • Primary Citation of Related Structures:  
    1ONG, 1ONH

  • PubMed Abstract: 

    A new beta-lactamase inhibitor, a methylidene penem having a 5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazine heterocyclic substituent at the C6 position with a Z configuration, irreversibly inhibits both class A and class C serine beta-lactamases with IC(50) values of 0.4 and 9.0 nM for TEM-1 and SHV-1 (class A), respectively, and 4.8 nM in AmpC (class C) beta-lactamases. The compound also inhibits irreversibly the class C extended-spectrum GC1 beta-lactamase (IC(50) = 6.2 nM). High-resolution crystallographic structures of a reaction intermediate of (5R)-(6Z)-6-(5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazin-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-3-carboxylic acid 1 with the SHV-1 beta-lactamase and with the GC1 beta-lactamase have been determined by X-ray diffraction to resolutions of 1.10 and 1.38 A, respectively. The two complexes were refined to crystallographic R-factors (R(free)) of 0.141 (0.186) and 0.138 (0.202), respectively. Cryoquenching of the reaction of 1 with each beta-lactamase crystal produced a common, covalently bound intermediate. After acylation of the serine, a nucleophilic attack by the departing thiolate on the C6' atom yielded a novel seven-membered 1,4-thiazepine ring having R stereochemistry at the new C7 moiety. The orientation of this ring in each complex differs by a 180 degrees rotation about the bond to the acylated serine. The acyl ester bond is stabilized to hydrolysis through resonance stabilization with the dihydrothiazepine ring and by low occupancy or disorder of hydrolytic water molecules. In the class A complex, the buried water molecule on the alpha-face of the ester bond appears to be loosely bound or absent. In the class C complex, a water molecule on the beta-face is disordered and poorly activated for hydrolysis. Here, the acyl intermediate is unable to assist its own hydrolysis, as is thought to occur with many class C substrates.


  • Organizational Affiliation

    Department of Molecular and Cell Biology, The University of Connecticut, Storrs, Connecticut 06269-3125, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
BETA-LACTAMASE SHV-1265Klebsiella pneumoniaeMutation(s): 0 
Gene Names: BLA
EC: 3.5.2.6
UniProt
Find proteins for P0AD64 (Klebsiella pneumoniae)
Explore P0AD64 
Go to UniProtKB:  P0AD64
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP0AD64
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
MA4
Query on MA4

Download Ideal Coordinates CCD File 
B [auth A],
C [auth A]
CYCLOHEXYL-HEXYL-BETA-D-MALTOSIDE
C24 H44 O11
WUCWJXGMSXTDAV-QKMCSOCLSA-N
WY4
Query on WY4

Download Ideal Coordinates CCD File 
D [auth A]7-(5,6-DIHYDRO-8H-IMIDAZO[2,1-C][1,4]OXAZIN-2-YL)-6-FORMYL-2,7-DIHYDRO- [1,4]THIAZEPINE-3-CARBOXYLIC ACID
C13 H13 N3 O4 S
CTKODGPKPNVQNS-GFCCVEGCSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
WY4 PDBBind:  1ONG IC50: 9 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.10 Å
  • R-Value Free: 0.186 
  • R-Value Work: 0.141 
  • R-Value Observed: 0.141 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 49.555α = 90
b = 55.183β = 90
c = 85.315γ = 90
Software Package:
Software NamePurpose
SHELXL-97refinement
SCALEPACKdata scaling
CNSrefinement
DENZOdata reduction
CNSphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2003-12-09
    Type: Initial release
  • Version 1.1: 2008-04-29
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2019-07-24
    Changes: Data collection, Derived calculations, Refinement description
  • Version 1.4: 2023-08-16
    Changes: Data collection, Database references, Derived calculations, Refinement description