3T4V

Crystal Structure of AlkB in complex with Fe(III) and N-Oxalyl-S-(2-napthalenemethyl)-L-cysteine


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.73 Å
  • R-Value Free: 0.202 
  • R-Value Work: 0.161 
  • R-Value Observed: 0.165 

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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Dynamic combinatorial mass spectrometry leads to inhibitors of a 2-oxoglutarate-dependent nucleic Acid demethylase.

Woon, E.C.Demetriades, M.Bagg, E.A.Aik, W.Krylova, S.M.Ma, J.H.Chan, M.Walport, L.J.Wegman, D.W.Dack, K.N.McDonough, M.A.Krylov, S.N.Schofield, C.J.

(2012) J Med Chem 55: 2173-2184

  • DOI: https://doi.org/10.1021/jm201417e
  • Primary Citation of Related Structures:  
    3T3Y, 3T4H, 3T4V

  • PubMed Abstract: 

    2-Oxoglutarate-dependent nucleic acid demethylases are of biological interest because of their roles in nucleic acid repair and modification. Although some of these enzymes are linked to physiology, their regulatory roles are unclear. Hence, there is a desire to develop selective inhibitors for them; we report studies on AlkB, which reveal it as being amenable to selective inhibition by small molecules. Dynamic combinatorial chemistry linked to mass spectrometric analyses (DCMS) led to the identification of lead compounds, one of which was analyzed by crystallography. Subsequent structure-guided studies led to the identification of inhibitors of improved potency, some of which were shown to be selective over two other 2OG oxygenases. The work further validates the use of the DCMS method and will help to enable the development of inhibitors of nucleic acid modifying 2OG oxygenases both for use as functional probes and, in the longer term, for potential therapeutic use.


  • Organizational Affiliation

    Chemistry Research Laboratory, Department of Chemistry, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Alpha-ketoglutarate-dependent dioxygenase AlkB206Escherichia coli K-12Mutation(s): 0 
Gene Names: aidDalkBb2212JW2200
EC: 1.14.11
UniProt
Find proteins for P05050 (Escherichia coli (strain K12))
Explore P05050 
Go to UniProtKB:  P05050
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP05050
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
MD3 PDBBind:  3T4V IC50: 500 (nM) from 1 assay(s)
Binding MOAD:  3T4V IC50: 500 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.73 Å
  • R-Value Free: 0.202 
  • R-Value Work: 0.161 
  • R-Value Observed: 0.165 
  • Space Group: P 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 37.07α = 76.33
b = 39.234β = 74.56
c = 40.261γ = 65.28
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
PHASERphasing
PHENIXrefinement
PDB_EXTRACTdata extraction
CrystalCleardata collection
HKL-2000data reduction
HKL-2000data scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2012-03-07
    Type: Initial release
  • Version 1.1: 2012-03-21
    Changes: Database references
  • Version 1.2: 2017-11-08
    Changes: Refinement description
  • Version 1.3: 2023-09-13
    Changes: Data collection, Database references, Derived calculations, Refinement description