3K4D

Crystal structure of E. coli beta-glucuronidase with the glucaro-d-lactam inhibitor bound


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.39 Å
  • R-Value Free: 0.237 
  • R-Value Work: 0.205 
  • R-Value Observed: 0.206 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Alleviating cancer drug toxicity by inhibiting a bacterial enzyme.

Wallace, B.D.Wang, H.Lane, K.T.Scott, J.E.Orans, J.Koo, J.S.Venkatesh, M.Jobin, C.Yeh, L.A.Mani, S.Redinbo, M.R.

(2010) Science 330: 831-835

  • DOI: https://doi.org/10.1126/science.1191175
  • Primary Citation of Related Structures:  
    3K46, 3K4A, 3K4D, 3LPF, 3LPG

  • PubMed Abstract: 

    The dose-limiting side effect of the common colon cancer chemotherapeutic CPT-11 is severe diarrhea caused by symbiotic bacterial β-glucuronidases that reactivate the drug in the gut. We sought to target these enzymes without killing the commensal bacteria essential for human health. Potent bacterial β-glucuronidase inhibitors were identified by high-throughput screening and shown to have no effect on the orthologous mammalian enzyme. Crystal structures established that selectivity was based on a loop unique to bacterial β-glucuronidases. Inhibitors were highly effective against the enzyme target in living aerobic and anaerobic bacteria, but did not kill the bacteria or harm mammalian cells. Finally, oral administration of an inhibitor protected mice from CPT-11-induced toxicity. Thus, drugs may be designed to inhibit undesirable enzyme activities in essential microbial symbiotes to enhance chemotherapeutic efficacy.


  • Organizational Affiliation

    Department of Chemistry, University of North Carolina, Chapel Hill, NC 27599, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Beta-glucuronidase
A, B
605Escherichia coli K-12Mutation(s): 0 
Gene Names: b1617gurAgusAJW1609uidA
EC: 3.2.1.31
UniProt
Find proteins for P05804 (Escherichia coli (strain K12))
Explore P05804 
Go to UniProtKB:  P05804
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP05804
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
EVA
Query on EVA

Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]
(2S,3R,4S,5R)-3,4,5-trihydroxy-6-oxopiperidine-2-carboxylic acid
C6 H9 N O6
YEWOHTVJCCDCCS-NTAGLIMJSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
EVA Binding MOAD:  3K4D Ki: 7750 (nM) from 1 assay(s)
PDBBind:  3K4D Ki: 7750 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.39 Å
  • R-Value Free: 0.237 
  • R-Value Work: 0.205 
  • R-Value Observed: 0.206 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 167.653α = 90
b = 76.971β = 124.98
c = 125.468γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
SCALEPACKdata scaling
MOLREPphasing
PHENIXrefinement
PDB_EXTRACTdata extraction
HKL-2000data collection
HKL-2000data reduction
HKL-2000data scaling
DENZOdata reduction

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2010-11-17
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Source and taxonomy, Version format compliance
  • Version 1.2: 2017-11-01
    Changes: Refinement description
  • Version 1.3: 2019-07-17
    Changes: Data collection, Refinement description
  • Version 1.4: 2023-09-06
    Changes: Data collection, Database references, Derived calculations, Refinement description