2cn8: Difference between revisions
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==Overview== | ==Overview== | ||
The protein kinase Chk2 (checkpoint kinase 2) is a major effector of the | 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. | ||
==Disease== | ==Disease== | ||
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[[Category: Non-specific serine/threonine protein kinase]] | [[Category: Non-specific serine/threonine protein kinase]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Oliver, A | [[Category: Oliver, A W.]] | ||
[[Category: Pearl, L | [[Category: Pearl, L H.]] | ||
[[Category: DBQ]] | [[Category: DBQ]] | ||
[[Category: MG]] | [[Category: MG]] | ||
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[[Category: tumour suppressor]] | [[Category: tumour suppressor]] | ||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:50:30 2008'' | ||
Revision as of 17:50, 21 February 2008
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CRYSTAL STRUCTURE OF HUMAN CHK2 IN COMPLEX WITH DEBROMOHYMENIALDISINE
OverviewOverview
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.
DiseaseDisease
Known diseases associated with this structure: Breast and colorectal cancer, susceptibility to OMIM:[604373], Breast cancer, susceptibility to OMIM:[604373], Li-Fraumeni syndrome OMIM:[604373], Osteosarcoma, somatic OMIM:[604373], Prostate cancer, familial OMIM:[604373]
About this StructureAbout this Structure
2CN8 is a Single protein structure of sequence from Homo sapiens with , and as ligands. Active as Non-specific serine/threonine protein kinase, with EC number 2.7.11.1 Known structural/functional Site: . Full crystallographic information is available from OCA.
ReferenceReference
Trans-activation of the DNA-damage signalling protein kinase Chk2 by T-loop exchange., Oliver AW, Paul A, Boxall KJ, Barrie SE, Aherne GW, Garrett MD, Mittnacht S, Pearl LH, EMBO J. 2006 Jul 12;25(13):3179-90. Epub 2006 Jun 22. PMID:16794575
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Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)
OCA- Pages with broken file links
- Homo sapiens
- Non-specific serine/threonine protein kinase
- Single protein
- Oliver, A W.
- Pearl, L H.
- DBQ
- MG
- NO3
- Activation segment
- Atp-binding
- Cancer
- Cds1
- Checkpoint
- Chek2
- Chk2
- Hypothetical protein
- Kinase
- Kinase domain
- Li-fraumeni syndrome
- Nucleotide-binding
- Phosphorylation
- Rad53
- Serine/threonine-protein kinase
- Transferase
- Tumour suppressor