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| Subject Categories:
Genome Stability & Dynamics
| Structural Biology
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The EMBO Journal
(2006) 25, 3179–3190, doi:10.1038/sj.emboj.7601209 Published online 22 June 2006
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| Trans-activation of the DNA-damage signalling protein kinase Chk2 by T-loop exchange |
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Antony W Oliver1, Angela Paul2, Katherine J Boxall3, S Elaine Barrie3, G Wynne Aherne3, Michelle D Garrett3, Sibylle Mittnacht2 and Laurence H Pearl1
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1 Cancer Research UK DNA Repair Enzymes Group, Section of Structural Biology, The Institute of Cancer Research, Chelsea, London, UK
2 Cancer Research UK Centre for Cell and Molecular Biology, The Institute of Cancer Research, Chelsea, London, UK
3 Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, Haddow Laboratories, Sutton, Surrey, UK
To whom correspondence should be addressed
Antony W Oliver, Cancer Research UK DNA Repair Enzymes Group, The Institute of Cancer Research, 237 Fulham Road, Chelsea, London SW3 6JB, UK. Tel.: +44 20 7153 5571; Fax: +44 20 6153 5457; E-mail: antony.oliver@icr.ac.uk Laurence H Pearl, Cancer Research UK DNA Repair Enzymes Group, The Institute of Cancer Research, 237 Fulham Road, Chelsea, London SW3 6JB, UK. Tel.: +44 20 7153 5571; Fax: +44 20 6153 5457; E-mail: laurence.pearl@icr.ac.uk
Received 8 February 2006; Accepted 31 May 2006; Published online 22 June 2006.
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| Abstract |
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| 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. |
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| Keywords: cancer, CHEK2, CHK2, inhibitor, kinase |
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