2CN8

Crystal structure of human Chk2 in complex with debromohymenialdisine


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.70 Å
  • R-Value Free: 0.271 
  • R-Value Work: 0.204 
  • R-Value Observed: 0.207 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Trans-Activation of the DNA-Damage Signalling Protein Kinase Chk2 by T-Loop Exchange

Oliver, A.W.Paul, A.Boxall, K.J.Barrie, S.E.Aherne, G.W.Garrett, M.D.Mittnacht, S.Pearl, L.H.

(2006) EMBO J 25: 3179

  • DOI: https://doi.org/10.1038/sj.emboj.7601209
  • Primary Citation of Related Structures:  
    2CN5, 2CN8

  • PubMed Abstract: 

    The protein kinase Chk2 (checkpoint kinase 2) is a major effector of the replication checkpoint. Chk2 activation is initiated by phosphorylation of Thr68, in the serine-glutamine/threonine-glutamine cluster domain (SCD), by ATM. The phosphorylated SCD-segment binds to the FHA domain of a second Chk2 molecule, promoting dimerisation of the protein and triggering phosphorylation of the activation segment/T-loop in the kinase domain. We have now determined the structure of the kinase domain of human Chk2 in complexes with ADP and a small-molecule inhibitor debromohymenialdisine. The structure reveals a remarkable dimeric arrangement in which T-loops are exchanged between protomers, to form an active kinase conformation in trans. Biochemical data suggest that this dimer is the biologically active state promoted by ATM-phosphorylation, and also suggests a mechanism for dimerisation-driven activation of Chk2 by trans-phosphorylation.


  • Organizational Affiliation

    Section of Structural Biology, Cancer Research UK DNA Repair Enzymes Group, The Institute of Cancer Research, Chelsea, London, UK. antony.oliver@icr.ac.uk


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
SERINE/THREONINE-PROTEIN KINASE CHK2329Homo sapiensMutation(s): 0 
EC: 2.7.11.1
UniProt & NIH Common Fund Data Resources
Find proteins for O96017 (Homo sapiens)
Explore O96017 
Go to UniProtKB:  O96017
PHAROS:  O96017
GTEx:  ENSG00000183765 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO96017
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
DBQ PDBBind:  2CN8 IC50: 3500 (nM) from 1 assay(s)
BindingDB:  2CN8 IC50: min: 183, max: 3500 (nM) from 2 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.70 Å
  • R-Value Free: 0.271 
  • R-Value Work: 0.204 
  • R-Value Observed: 0.207 
  • Space Group: P 32 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 88.65α = 90
b = 88.65β = 90
c = 88.897γ = 120
Software Package:
Software NamePurpose
REFMACrefinement
MOSFLMdata reduction
SCALAdata scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2006-06-28
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Advisory, Version format compliance
  • Version 1.2: 2023-12-13
    Changes: Data collection, Database references, Derived calculations, Other, Refinement description