2CN8

Crystal structure of human Chk2 in complex with debromohymenialdisine

Summary for 2CN8

• Entry DOI: 10.2210/pdb2cn8/pdb
• Related: 1GXC 2CN5
• Descriptor: SERINE/THREONINE-PROTEIN KINASE CHK2, MAGNESIUM ION, NITRATE ION, ... (5 entities in total)
• Functional Keywords: atp-binding, transferase, kinase domain, phosphorylation, tumour suppressor, activation segment, li-fraumeni syndrome, serine/threonine-protein kinase, chk2, cds1, rad53, chek2, kinase, cancer, checkpoint, nucleotide-binding, hypothetical protein
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Isoform 2: Nucleus. Isoform 4: Nucleus. Isoform 7: Nucleus. Isoform 9: Nucleus. Isoform 12: Nucleus. Nucleus, PML body: O96017
• Total number of polymer chains: 1
• Total formula weight: 37443.39

Authors

Oliver, A.W.,Pearl, L.H. (deposition date: 2006-05-18, release date: 2006-06-28, Last modification date: 2023-12-13)

Primary citation

Oliver, A.W.,Paul, A.,Boxall, K.J.,Barrie, S.E.,Aherne, G.W.,Garrett, M.D.,Mittnacht, S.,Pearl, L.H.
Trans-Activation of the DNA-Damage Signalling Protein Kinase Chk2 by T-Loop Exchange
Embo J., 25:3179-, 2006

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.

PubMed: 16794575
DOI: 10.1038/SJ.EMBOJ.7601209

Experimental method

X-RAY DIFFRACTION (2.7 Å)