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PDBsum entry 1blx
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Complex (inhibitor protein/kinase)
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PDB id
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1blx
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Crystal structure of the complex of the cyclin d-Dependent kinase cdk6 bound to the cell-Cycle inhibitor p19ink4d.
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Authors
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D.H.Brotherton,
V.Dhanaraj,
S.Wick,
L.Brizuela,
P.J.Domaille,
E.Volyanik,
X.Xu,
E.Parisini,
B.O.Smith,
S.J.Archer,
M.Serrano,
S.L.Brenner,
T.L.Blundell,
E.D.Laue.
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Ref.
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Nature, 1998,
395,
244-250.
[DOI no: ]
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PubMed id
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Abstract
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The crystal structure of the cyclin D-dependent kinase Cdk6 bound to the p19
INK4d protein has been determined at 1.9 A resolution. The results provide the
first structural information for a cyclin D-dependent protein kinase and show
how the INK4 family of CDK inhibitors bind. The structure indicates that the
conformational changes induced by p19INK4d inhibit both productive binding of
ATP and the cyclin-induced rearrangement of the kinase from an inactive to an
active conformation. The structure also shows how binding of an INK4 inhibitor
would prevent binding of p27Kip1, resulting in its redistribution to other CDKs.
Identification of the critical residues involved in the interaction explains how
mutations in Cdk4 and p16INK4a result in loss of kinase inhibition and cancer.
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Figure 2.
Figure 2 Three-dimensional structure of the p19^INK4d/Cdk6
complex. a, Stereo view of the C  trace
of the p19^INK4d/Cdk6 structure. Every tenth C atom
is indicated by a solid ball. b, Schematic drawing of the same
complex after rotation by 90° about the x axis. c, P19^INK4d and
p27^Kip1 prevent each other binding to the CDK subunit in cyclin
D/Cdk6. The structure in c is rotated 20° about the z axis
compared to b. In a and b p19^INK4d is coloured yellow, apart
from helix 3
(residues 46-50), which is red. The C-terminal domain of Cdk6 is
coloured light blue, whereas the N-terminal domain, which
undergoes extensive movement, is dark blue. In c, p19^INK4d is
coloured yellow, Cdk6 is light/dark blue, p27^Kip1 is red and
cyclin A is green. p27^Kip1 and cyclin A from the
p27^Kip1/cyclin A/Cdk2 structure^40 were superimposed, as
described in Fig. 5a, on p19^INK4d/Cdk6 (r.m.s. deviation was
0.46 ? over 70 residues). Figures 2 and 5a, b were produced
using the programs MOLSCRIPT47 and RASTER3D^48.
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Figure 5.
Figure 5 Comparison of ATP-binding sites in different
kinases. a, Comparison of the structure of p19^INK4d/Cdk6 with
those of Cdk2 (ref. 15) and Cdk2 from the cyclin A complex16,17.
Cdk6 was superimposed on Cdk2 (r.m.s. deviation was 0.56 ? over
70 residues) and Cdk2 from the cyclin A complex (r.m.s.
deviation was 0.49 ? over 70 residues) by aligning the C atoms
in the -helices
in the C-terminal domain of both proteins. Loop L5 and the
linker (loop L7) (Fig. 3c), which anchor the N- and C-terminal
domains together, are labelled. b, The same structures, showing
only the N-terminal domain, illustrating the changes in position
of the N-terminal  -sheet
and helix 1.
In both a and b, the N-terminal domains and T-loop are coloured
red (Cdk2), yellow (Cdk2 from the cyclin A complex) and blue
(Cdk6); other regions of all three proteins are coloured grey.
In b, helices 3
and 5
of cyclin A, which interact with PSTAIRE helix 1
in cyclin A/Cdk2 (refs 16, 17), are green. c, The ATP-binding
site in Cdk6. Lys 29, His 100 and Asp 102, which together might
inhibit ATP binding, are labelled, as are key active-site
residues and the phosphate-binding loop L2. ATP, from the active
Cdk2/cyclin A complex17, is superimposed on the structure with
the N1 and N6 adenine nitrogens making conserved hydrogen bonds
with the carbonyl of Glu 99 and amide of Val 101,
respectively17,34. The structures of Cdk6 and ATP are yellow and
green, respectively. Carbon, nitrogen, oxygen and phosphorus
atoms are yellow, blue, red and yellow, respectively. The
structure of Cdk2 from the cyclin A/Cdk2 complex17 is blue.
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The above figures are
reprinted
by permission from Macmillan Publishers Ltd:
Nature
(1998,
395,
244-250)
copyright 1998.
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Secondary reference #1
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Title
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Identification and role of adenylyl cyclase in auxin signalling in higher plants.
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Authors
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T.Ichikawa,
Y.Suzuki,
I.Czaja,
C.Schommer,
A.Lessnick,
J.Schell,
R.Walden.
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Ref.
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Nature, 1998,
396,
390.
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PubMed id
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