 |
PDBsum entry 2cn5
|
|
|
|
References listed in PDB file
|
 |
|
Key reference
|
|
|
Title
|
|
Trans-Activation of the DNA-Damage signalling protein kinase chk2 by t-Loop exchange.
|
|
|
Authors
|
|
A.W.Oliver,
A.Paul,
K.J.Boxall,
S.E.Barrie,
G.W.Aherne,
M.D.Garrett,
S.Mittnacht,
L.H.Pearl.
|
|
|
Ref.
|
|
EMBO J, 2006,
25,
3179-3190.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
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.
|
|
|
|
|
|
|
|
Figure 2.
Figure 2 Structure of Chk2 kinase domain. Secondary structure
cartoon of the binary complex of CHK2-KD with ADP. The
glycine-rich loop is coloured pink, the DFG and APE motifs red,
and the T-loop yellow. Secondary structure elements
corresponding to  -strands
are coloured blue and  -helices
cyan. ADP is shown as a 'stick' model. The catalytic residue
Asp347, conserved residues Lys249 and Glu373, and
autophosphorylation sites Thr383 and Thr387 are also
highlighted. Molecular images in this and subsequent figures
were generated using PyMOL (www.pymol.org).
|
|
Figure 7.
Figure 7 Chk2 T-loop autophosphorylation sites do not resemble
endogenous substrates. Alignment of endogenous Chk2 substrate
sequences (CDC25A, CDC25C, BRCA-1, E2F-1, PML) with an optimised
substrate sequence (Chk2-TIDE) and T-loop autophosphorylation
sites. For each sequence, the residue number of the first amino
acid is listed (res). The autophosphorylation sites of Chk2
overlap, as indicated by the underlined regions. The 'p' column
header indicates the phosphorylated amino acid.
|
|
|
|
|
|
The above figures are
reprinted
from an Open Access publication published by Macmillan Publishers Ltd:
EMBO J
(2006,
25,
3179-3190)
copyright 2006.
|
|
|
|
|
|
|
