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Contents |
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* Residue conservation analysis
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Enzyme class:
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Chain A:
E.C.2.7.11.22
- cyclin-dependent kinase.
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Reaction:
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1.
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L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H+
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2.
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L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H+
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L-seryl-[protein]
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+
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ATP
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=
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O-phospho-L-seryl-[protein]
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+
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ADP
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+
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H(+)
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L-threonyl-[protein]
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+
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ATP
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=
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O-phospho-L-threonyl-[protein]
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+
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ADP
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+
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H(+)
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Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
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DOI no:
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Nature
395:237-243
(1998)
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PubMed id:
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Structural basis for inhibition of the cyclin-dependent kinase Cdk6 by the tumour suppressor p16INK4a.
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A.A.Russo,
L.Tong,
J.O.Lee,
P.D.Jeffrey,
N.P.Pavletich.
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ABSTRACT
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The cyclin-dependent kinases 4 and 6 (Cdk4/6) that control the G1 phase of the
cell cycle and their inhibitor, the p16INK4a tumour suppressor, have a central
role in cell proliferation and in tumorigenesis. The structures of Cdk6 bound to
p16INK4a and to the related p19INK4d reveal that the INK4 inhibitors bind next
to the ATP-binding site of the catalytic cleft, opposite where the activating
cyclin subunit binds. They prevent cyclin binding indirectly by causing
structural changes that propagate to the cyclin-binding site. The INK4
inhibitors also distort the kinase catalytic cleft and interfere with ATP
binding, which explains how they can inhibit the preassembled Cdk4/6-cyclin D
complexes as well. Tumour-derived mutations in INK4a and Cdk4 map to interface
contacts, solidifying the role of CDK binding and inhibition in the tumour
suppressor activity of p16INK4a.
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Selected figure(s)
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Figure 1.
Figure 1 The INK4 inhibitors bind to one side of the
catalytic cleft of Cdk6, and interact with both the N and C
lobes. a, b, Schematic representation of the p16-Cdk6 complex in
two orthogonal views, with the ankyrin repeats numbered. c, View
of the p19-Cdk6 complex in an orientation equivalent to that in
b. Figures were made with the programs MOLSCRIPT50 and
RASTER3D^51.
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Figure 3.
Figure 3 Conserved hydrogen-bond networks by the second and
third ankyrin repeats of p16 and p19 have a central role in Cdk6
binding. a, Cross-section of the complex showing the contacts
between Cdk6 and the second ankyrin repeat. b, Cross-section
showing the third ankyrin repeat. Only the hydrogen-bond
contacts conserved in the p16-Cdk6 and the p19-Cdk6 complexes
are shown (red dotted lines). The figures show the p19-Cdk6
complex, as the atomic positions of this 2.8-?-refined model are
of higher precision than those of the 3.4-?-refined p16-Cdk6
complex. INK4 residues are labelled first with their p19 numbers
and second with their p16 numbers, separated by a slash. The
secondary structure labels of Cdk6 are according to Cdk2 (ref.
30).
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The above figures are
reprinted
by permission from Macmillan Publishers Ltd:
Nature
(1998,
395,
237-243)
copyright 1998.
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Figures were
selected
by an automated process.
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Literature references that cite this PDB file's key reference
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PubMed id
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Reference
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H.J.Zhang,
M.K.Siu,
M.C.Yeung,
L.L.Jiang,
V.C.Mak,
H.Y.Ngan,
O.G.Wong,
H.Q.Zhang,
and
A.N.Cheung
(2011).
Overexpressed PAK4 promotes proliferation, migration and invasion of choriocarcinoma.
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Carcinogenesis,
32,
765-771.
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C.V.Kuny,
K.Chinchilla,
M.R.Culbertson,
and
R.F.Kalejta
(2010).
Cyclin-dependent kinase-like function is shared by the beta- and gamma- subset of the conserved herpesvirus protein kinases.
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| |
PLoS Pathog,
6,
0.
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C.de Torre,
and
J.Martínez-Escribano
(2010).
Novel CDKN2A mutation detected in Spanish melanoma pedigree.
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| |
Exp Dermatol,
19,
e333-e335.
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N.Fahham,
S.Sardari,
S.N.Ostad,
B.Vaziri,
and
M.H.Ghahremani
(2010).
C-terminal domain of p16(INK4a) is adequate in inducing cell cycle arrest, growth inhibition and CDK4/6 interaction similar to the full length protein in HT-1080 fibrosarcoma cells.
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J Cell Biochem,
111,
1598-1606.
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Y.Yamada,
A.Nakata,
M.A.Yoshida,
Y.Shimada,
Y.Oghiso,
and
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(2010).
Implication of p16 inactivation in tumorigenic activity of respiratory epithelial cell lines and adenocarcinoma cell line established from plutonium-induced lung tumor in rat.
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| |
In Vitro Cell Dev Biol Anim,
46,
477-486.
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C.G.Mullighan,
J.Zhang,
R.C.Harvey,
J.R.Collins-Underwood,
B.A.Schulman,
L.A.Phillips,
S.K.Tasian,
M.L.Loh,
X.Su,
W.Liu,
M.Devidas,
S.R.Atlas,
I.M.Chen,
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M.Smith,
J.R.Downing,
S.P.Hunger,
and
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(2009).
JAK mutations in high-risk childhood acute lymphoblastic leukemia.
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| |
Proc Natl Acad Sci U S A,
106,
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C.Kannengiesser,
S.Brookes,
A.G.del Arroyo,
D.Pham,
J.Bombled,
M.Barrois,
O.Mauffret,
M.F.Avril,
A.Chompret,
G.M.Lenoir,
A.Sarasin,
G.Peters,
B.Bressac-de Paillerets,
F.Boitier,
V.Bonadonna,
J.M.Bonnetblanc,
J.Chiesa,
I.Coupier,
S.Dalle,
F.Grange,
B.Guillot,
P.Joly,
C.Lasset,
D.Leroux,
J.M.Limacher,
M.Longy,
T.Martin-Denavit,
L.Thomas,
and
P.Vabres
(2009).
Functional, structural, and genetic evaluation of 20 CDKN2A germ line mutations identified in melanoma-prone families or patients.
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Hum Mutat,
30,
564-574.
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J.Aguirre-Hernández,
B.S.Milne,
C.Queen,
P.C.O'Brien,
T.Hoather,
S.Haugland,
M.A.Ferguson-Smith,
J.M.Dobson,
and
D.R.Sargan
(2009).
Disruption of chromosome 11 in canine fibrosarcomas highlights an unusual variability of CDKN2B in dogs.
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BMC Vet Res,
5,
27.
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N.Fahham,
M.H.Ghahremani,
S.Sardari,
B.Vaziri,
and
S.N.Ostad
(2009).
Simulation of Different Truncated p16 Forms and In Silico Study of Interaction with Cdk4.
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Cancer Inform,
7,
1.
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P.DeInnocentes,
P.Agarwal,
and
R.C.Bird
(2009).
Phenotype-rescue of cyclin-dependent kinase inhibitor p16/INK4A defects in a spontaneous canine cell model of breast cancer.
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J Cell Biochem,
106,
491-505.
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T.P.Sun,
and
S.Y.Shieh
(2009).
Human FEM1B is required for Rad9 recruitment and CHK1 activation in response to replication stress.
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| |
Oncogene,
28,
1971-1981.
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Y.Yang,
X.Wang,
C.A.Hawkins,
K.Chen,
J.Vaynberg,
X.Mao,
Y.Tu,
X.Zuo,
J.Wang,
Y.X.Wang,
C.Wu,
N.Tjandra,
and
J.Qin
(2009).
Structural Basis of Focal Adhesion Localization of LIM-only Adaptor PINCH by Integrin-linked Kinase.
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| |
J Biol Chem,
284,
5836-5844.
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A.Forget,
O.Ayrault,
W.den Besten,
M.L.Kuo,
C.J.Sherr,
and
M.F.Roussel
(2008).
Differential post-transcriptional regulation of two Ink4 proteins, p18 Ink4c and p19 Ink4d.
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Cell Cycle,
7,
3737-3746.
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A.Hecker,
R.Lopreiato,
M.Graille,
B.Collinet,
P.Forterre,
D.Libri,
and
H.van Tilbeurgh
(2008).
Structure of the archaeal Kae1/Bud32 fusion protein MJ1130: a model for the eukaryotic EKC/KEOPS subcomplex.
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EMBO J,
27,
2340-2351.
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PDB code:
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J.B.Koorstra,
S.R.Hustinx,
G.J.Offerhaus,
and
A.Maitra
(2008).
Pancreatic carcinogenesis.
|
| |
Pancreatology,
8,
110-125.
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J.Li,
B.Warner,
B.C.Casto,
T.J.Knobloch,
and
C.M.Weghorst
(2008).
Tumor suppressor p16(INK4A)/Cdkn2a alterations in 7, 12-dimethylbenz(a)anthracene (DMBA)-induced hamster cheek pouch tumors.
|
| |
Mol Carcinog,
47,
733-738.
|
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M.G.Lerner,
K.L.Meagher,
and
H.A.Carlson
(2008).
Automated clustering of probe molecules from solvent mapping of protein surfaces: new algorithms applied to hot-spot mapping and structure-based drug design.
|
| |
J Comput Aided Mol Des,
22,
727-736.
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M.K.James,
A.Ray,
D.Leznova,
and
S.W.Blain
(2008).
Differential modification of p27Kip1 controls its cyclin D-cdk4 inhibitory activity.
|
| |
Mol Cell Biol,
28,
498-510.
|
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T.M.Bandeiras,
R.C.Hillig,
P.M.Matias,
U.Eberspaecher,
J.Fanghänel,
M.Thomaz,
S.Miranda,
K.Crusius,
V.Pütter,
P.Amstutz,
M.Gulotti-Georgieva,
H.K.Binz,
C.Holz,
A.A.Schmitz,
C.Lang,
P.Donner,
U.Egner,
M.A.Carrondo,
and
B.Müller-Tiemann
(2008).
Structure of wild-type Plk-1 kinase domain in complex with a selective DARPin.
|
| |
Acta Crystallogr D Biol Crystallogr,
64,
339-353.
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PDB code:
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Y.W.Lu,
and
E.K.Tan
(2008).
Molecular biology changes associated with LRRK2 mutations in Parkinson's disease.
|
| |
J Neurosci Res,
86,
1895-1901.
|
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|
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A.Mahajan,
Y.Guo,
C.Yuan,
C.M.Weghorst,
M.D.Tsai,
and
J.Li
(2007).
Dissection of protein-protein interaction and CDK4 inhibition in the oncogenic versus tumor suppressing functions of gankyrin and P16.
|
| |
J Mol Biol,
373,
990.
|
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A.Schweizer,
H.Roschitzki-Voser,
P.Amstutz,
C.Briand,
M.Gulotti-Georgieva,
E.Prenosil,
H.K.Binz,
G.Capitani,
A.Baici,
A.Plückthun,
and
M.G.Grütter
(2007).
Inhibition of caspase-2 by a designed ankyrin repeat protein: specificity, structure, and inhibition mechanism.
|
| |
Structure,
15,
625-636.
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PDB code:
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E.Souza-Rodrígues,
J.M.Estanyol,
E.Friedrich-Heineken,
E.Olmedo,
J.Vera,
N.Canela,
S.Brun,
N.Agell,
U.Hübscher,
O.Bachs,
and
M.Jaumot
(2007).
Proteomic analysis of p16ink4a-binding proteins.
|
| |
Proteomics,
7,
4102-4111.
|
|
|
|
|
|
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F.G.Whitby,
and
C.P.Hill
(2007).
A versatile platform for inactivation and destruction.
|
| |
Structure,
15,
137-138.
|
|
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|
|
|
|
O.Fedorov,
B.Marsden,
V.Pogacic,
P.Rellos,
S.Müller,
A.N.Bullock,
J.Schwaller,
M.Sundström,
and
S.Knapp
(2007).
A systematic interaction map of validated kinase inhibitors with Ser/Thr kinases.
|
| |
Proc Natl Acad Sci U S A,
104,
20523-20528.
|
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PDB code:
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P.P.Joshi,
M.V.Kulkarni,
B.K.Yu,
K.R.Smith,
D.L.Norton,
W.Veelen,
J.W.Höppener,
and
D.S.Franklin
(2007).
Simultaneous downregulation of CDK inhibitors p18(Ink4c) and p27(Kip1) is required for MEN2A-RET-mediated mitogenesis.
|
| |
Oncogene,
26,
554-570.
|
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|
|
|
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Y.C.Lin,
M.B.Diccianni,
Y.Kim,
H.H.Lin,
C.H.Lee,
R.J.Lin,
S.H.Joo,
J.Li,
T.J.Chuang,
A.S.Yang,
H.H.Kuo,
M.D.Tsai,
and
A.L.Yu
(2007).
Human p16gamma, a novel transcriptional variant of p16(INK4A), coexpresses with p16(INK4A) in cancer cells and inhibits cell-cycle progression.
|
| |
Oncogene,
26,
7017-7027.
|
|
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|
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Y.Nakamura,
K.Nakano,
T.Umehara,
M.Kimura,
Y.Hayashizaki,
A.Tanaka,
M.Horikoshi,
B.Padmanabhan,
and
S.Yokoyama
(2007).
Structure of the oncoprotein gankyrin in complex with S6 ATPase of the 26S proteasome.
|
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Structure,
15,
179-189.
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PDB codes:
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G.Interlandi,
G.Settanni,
and
A.Caflisch
(2006).
Unfolding transition state and intermediates of the tumor suppressor p16INK4a investigated by molecular dynamics simulations.
|
| |
Proteins,
64,
178-192.
|
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I.F.Mata,
W.J.Wedemeyer,
M.J.Farrer,
J.P.Taylor,
and
K.A.Gallo
(2006).
LRRK2 in Parkinson's disease: protein domains and functional insights.
|
| |
Trends Neurosci,
29,
286-293.
|
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J.Joy,
N.Nalabothula,
M.Ghosh,
O.Popp,
M.Jochum,
W.Machleidt,
S.Gil-Parrado,
and
T.A.Holak
(2006).
Identification of calpain cleavage sites in the G1 cyclin-dependent kinase inhibitor p19(INK4d).
|
| |
Biol Chem,
387,
329-335.
|
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J.Sridhar,
N.Akula,
and
N.Pattabiraman
(2006).
Selectivity and potency of cyclin-dependent kinase inhibitors.
|
| |
AAPS J,
8,
E204-E221.
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K.E.Knudsen,
J.A.Diehl,
C.A.Haiman,
and
E.S.Knudsen
(2006).
Cyclin D1: polymorphism, aberrant splicing and cancer risk.
|
| |
Oncogene,
25,
1620-1628.
|
|
|
|
|
|
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K.Nilsson,
and
G.Landberg
(2006).
Subcellular localization, modification and protein complex formation of the cdk-inhibitor p16 in Rb-functional and Rb-inactivated tumor cells.
|
| |
Int J Cancer,
118,
1120-1125.
|
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|
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|
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O.Villacañas,
and
J.Rubio-Martinez
(2006).
Reducing CDK4/6-p16(INK4a) interface. Computational alanine scanning of a peptide bound to CDK6 protein.
|
| |
Proteins,
63,
797-810.
|
|
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|
|
|
|
W.A.Braden,
J.M.Lenihan,
Z.Lan,
K.S.Luce,
W.Zagorski,
E.Bosco,
M.F.Reed,
J.G.Cook,
and
E.S.Knudsen
(2006).
Distinct action of the retinoblastoma pathway on the DNA replication machinery defines specific roles for cyclin-dependent kinase complexes in prereplication complex assembly and S-phase progression.
|
| |
Mol Cell Biol,
26,
7667-7681.
|
|
|
|
|
|
|
A.Kohl,
P.Amstutz,
P.Parizek,
H.K.Binz,
C.Briand,
G.Capitani,
P.Forrer,
A.Plückthun,
and
M.G.Grütter
(2005).
Allosteric inhibition of aminoglycoside phosphotransferase by a designed ankyrin repeat protein.
|
| |
Structure,
13,
1131-1141.
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PDB code:
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A.Schulte,
N.Czudnochowski,
M.Barboric,
A.Schönichen,
D.Blazek,
B.M.Peterlin,
and
M.Geyer
(2005).
Identification of a cyclin T-binding domain in Hexim1 and biochemical analysis of its binding competition with HIV-1 Tat.
|
| |
J Biol Chem,
280,
24968-24977.
|
|
|
|
|
|
|
B.Y.Choi,
H.S.Choi,
K.Ko,
Y.Y.Cho,
F.Zhu,
B.S.Kang,
S.P.Ermakova,
W.Y.Ma,
A.M.Bode,
and
Z.Dong
(2005).
The tumor suppressor p16(INK4a) prevents cell transformation through inhibition of c-Jun phosphorylation and AP-1 activity.
|
| |
Nat Struct Mol Biol,
12,
699-707.
|
|
|
|
|
|
|
D.Tobi,
and
I.Bahar
(2005).
Structural changes involved in protein binding correlate with intrinsic motions of proteins in the unbound state.
|
| |
Proc Natl Acad Sci U S A,
102,
18908-18913.
|
|
|
|
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|
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J.Li,
A.El-Naggar,
and
L.Mao
(2005).
Promoter methylation of p16INK4a, RASSF1A, and DAPK is frequent in salivary adenoid cystic carcinoma.
|
| |
Cancer,
104,
771-776.
|
|
|
|
|
|
|
P.Amstutz,
H.K.Binz,
P.Parizek,
M.T.Stumpp,
A.Kohl,
M.G.Grütter,
P.Forrer,
and
A.Plückthun
(2005).
Intracellular kinase inhibitors selected from combinatorial libraries of designed ankyrin repeat proteins.
|
| |
J Biol Chem,
280,
24715-24722.
|
|
|
|
|
|
|
P.Kaldis
(2005).
The N-terminal peptide of the Kaposi's sarcoma-associated herpesvirus (KSHV)-cyclin determines substrate specificity.
|
| |
J Biol Chem,
280,
11165-11174.
|
|
|
|
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|
|
R.Halaban
(2005).
Rb/E2F: a two-edged sword in the melanocytic system.
|
| |
Cancer Metastasis Rev,
24,
339-356.
|
|
|
|
|
|
|
X.H.Pei,
and
Y.Xiong
(2005).
Biochemical and cellular mechanisms of mammalian CDK inhibitors: a few unresolved issues.
|
| |
Oncogene,
24,
2787-2795.
|
|
|
|
|
|
|
A.C.Lim,
Z.Hou,
C.P.Goh,
and
R.Z.Qi
(2004).
Protein kinase CK2 is an inhibitor of the neuronal Cdk5 kinase.
|
| |
J Biol Chem,
279,
46668-46673.
|
|
|
|
|
|
|
B.A.Manjasetty,
C.Quedenau,
V.Sievert,
K.Büssow,
F.Niesen,
H.Delbrück,
and
U.Heinemann
(2004).
X-ray structure of human gankyrin, the product of a gene linked to hepatocellular carcinoma.
|
| |
Proteins,
55,
214-217.
|
|
|
PDB code:
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|
|
B.Padmanabhan,
N.Adachi,
K.Kataoka,
and
M.Horikoshi
(2004).
Crystal structure of the homolog of the oncoprotein gankyrin, an interactor of Rb and CDK4/6.
|
| |
J Biol Chem,
279,
1546-1552.
|
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PDB code:
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Med Klin (Munich),
94,
233-238.
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S.G.Sedgwick,
and
S.J.Smerdon
(1999).
The ankyrin repeat: a diversity of interactions on a common structural framework.
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Trends Biochem Sci,
24,
311-316.
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T.Huxford,
S.Malek,
and
G.Ghosh
(1999).
Structure and mechanism in NF-kappa B/I kappa B signaling.
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Cold Spring Harb Symp Quant Biol,
64,
533-540.
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U.Schulze-Gahmen,
J.U.Jung,
and
S.H.Kim
(1999).
Crystal structure of a viral cyclin, a positive regulator of cyclin-dependent kinase 6.
|
| |
Structure,
7,
245-254.
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PDB code:
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The most recent references are shown first.
Citation data come partly from CiteXplore and partly
from an automated harvesting procedure. Note that this is likely to be
only a partial list as not all journals are covered by
either method. However, we are continually building up the citation data
so more and more references will be included with time.
Where a reference describes a PDB structure, the PDB
code is
shown on the right.
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Links
