 |
PDBsum entry 1ap7
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Cell cycle inhibitor
|
PDB id
|
|
|
|
1ap7
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Structure of the cyclin-Dependent kinase inhibitor p19ink4d.
|
|
|
Authors
|
|
F.Y.Luh,
S.J.Archer,
P.J.Domaille,
B.O.Smith,
D.Owen,
D.H.Brotherton,
A.R.Raine,
X.Xu,
L.Brizuela,
S.L.Brenner,
E.D.Laue.
|
|
|
Ref.
|
|
Nature, 1997,
389,
999.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
In cancer, the biochemical pathways that are dominated by the two
tumour-suppressor proteins, p53 and Rb, are the most frequently disrupted.
Cyclin D-dependent kinases phosphorylate Rb to control its activity and they
are, in turn, specifically inhibited by the Ink4 family of cyclin-dependent
kinase inhibitors (CDKIs) which cause arrest at the G1 phase of the cell cycle.
Mutations in Rb, cyclin D1, its catalytic subunit Cdk4, and the CDKI p16Ink4a,
which alter the protein or its level of expression, are all strongly implicated
in cancer. This suggests that the Rb 'pathway' is of particular importance. Here
we report the structure of the p19Ink4d protein, determined by NMR spectroscopy.
The structure indicates that most mutations to the p16Ink4a gene, which result
in loss of function, are due to incorrectly folded and/or insoluble proteins. We
propose a model for the interaction of Ink4 proteins with D-type cyclin-Cdk4/6
complexes that might provide a basis for the design of therapeutics against
cancer. The sequences of the Ink4 family of CDKIs are highly conserved
|
|
|
|
|
|
|
|
Figure 1.
Figure 1 Amino-acid sequence of the mouse p19^Ink4d protein
showing the homology between different ankyrin repeats (defined
as i. n ref. 7, but aligned according to the structure) and
between the different members of the Ink4 family of
cyclin-dependent kinase inhibitors. Arrows and rectangles
indicate the approximate positions of the  -strands
and  -helices,
respectively. Selected conserved residues are coloured yellow
(core hydrophobic), orange (aspartate and asparagine), green
(glycine and proline), red (Asp 71), magenta (histidine) and
blue (Lys 43) (see text for details).
|
|
Figure 3.
Figure 3 a, Comparison of the structure of p19^Ink4d closest
to the mean with that of 53BP2. The structures are shown in the
same orientation as those in Fig. 2 and the C carbons
of structurally equivalent residues in ankyrins III and IV from
p19^Ink4d and II and III from p53BP2 have been superimposed. The
surface-exposed residues of the sequence corresponding to the
p16^Ink4a peptide fragment (residues 80-99), previously shown
partially to mimic the activity of the intact protein, are shown
in yellow (ref. 22, and S. Wick, M. Dubay and L.B., unpublished
results). The side chains of residues 91 and 92, which, based on
alanine scanning mutagenesis in the peptide^22, most influence
the interaction with Cdk4 and Cdk6, are shown in dark blue. b,
Protein surfaces of the same p19^Ink4d structure (but now
rotated  55
? about the y-axis compared to that shown in a and Fig. 2) and a
model of Cdk4/cyclin D1 (B.O.S., unpublished). Cdk4 is shown in
white, cyclin D1 in purple, and Lys 22, Arg 24 and residues
95-97 of Cdk4 are in red; a yellow arrow indicates the position
of the active site in Cdk4. These plots were generated using
MOLSCRIPT29 and GRASP30.
|
|
|
|
|
|
The above figures are
reprinted
by permission from Macmillan Publishers Ltd:
Nature
(1997,
389,
999-0)
copyright 1997.
|
|
|
|
|
|
|
