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293 a.a.
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155 a.a.
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233 a.a.
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* Residue conservation analysis
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PDB id:
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Cell cycle, signaling protein
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Title:
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Structure of a p18(ink4c)-cdk6-k-cyclin ternary complex
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Structure:
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Cyclin-dependent kinase 6. Chain: a, e. Synonym: cell division protein kinase 6, protein kinase cdk6. Engineered: yes. Cyclin-dependent kinase 6 inhibitor. Chain: b, f. Synonym: p18(ink4c), cyclin-dependent kinase inhibitor 2c, p18, inhibits cdk4, cyclin-dependent kinase 4 inhibitor c, p18-ink4c. Engineered: yes.
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: cyclin-dependent kinase 6. Expressed in: unidentified baculovirus. Expression_system_taxid: 10469. Gene: p18(ink4c). Expressed in: escherichia coli. Expression_system_taxid: 562.
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Biol. unit:
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Hexamer (from
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Resolution:
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2.90Å
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R-factor:
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0.224
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R-free:
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0.262
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Authors:
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P.D.Jeffrey,L.Tong,N.P.Pavletich
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Key ref:
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P.D.Jeffrey
et al.
(2000).
Structural basis of inhibition of CDK-cyclin complexes by INK4 inhibitors.
Genes Dev,
14,
3115-3125.
PubMed id:
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Date:
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24-Oct-00
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Release date:
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10-Jan-01
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PROCHECK
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Headers
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References
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Q00534
(CDK6_HUMAN) -
Cyclin-dependent kinase 6 from Homo sapiens
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Seq:
Struc:
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326 a.a.
293 a.a.
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Enzyme class:
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Chains A, E:
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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Genes Dev
14:3115-3125
(2000)
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PubMed id:
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Structural basis of inhibition of CDK-cyclin complexes by INK4 inhibitors.
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P.D.Jeffrey,
L.Tong,
N.P.Pavletich.
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ABSTRACT
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The cyclin-dependent kinases 4 and 6 (Cdk4/6) that drive progression through the
G(1) phase of the cell cycle play a central role in the control of cell
proliferation, and CDK deregulation is a frequent event in cancer. Cdk4/6 are
regulated by the D-type cyclins, which bind to CDKs and activate the kinase, and
by the INK4 family of inhibitors. INK4 proteins can bind both monomeric CDK,
preventing its association with a cyclin, and also the CDK-cyclin complex,
forming an inactive ternary complex. In vivo, binary INK4-Cdk4/6 complexes are
more abundant than ternary INK4-Cdk4/6-cyclinD complexes, and it has been
suggested that INK4 binding may lead to the eventual dissociation of the cyclin.
Here we present the 2.9-A crystal structure of the inactive ternary complex
between Cdk6, the INK4 inhibitor p18(INK4c), and a D-type viral cyclin. The
structure reveals that p18(INK4c) inhibits the CDK-cyclin complex by distorting
the ATP binding site and misaligning catalytic residues. p18(INK4c) also
distorts the cyclin-binding site, with the cyclin remaining bound at an
interface that is substantially reduced in size. These observations support the
model that INK4 binding weakens the cyclin's affinity for the CDK. This
structure also provides insights into the specificity of the D-type cyclins for
Cdk4/6.
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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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B.B.Au-Yeung,
S.Deindl,
L.Y.Hsu,
E.H.Palacios,
S.E.Levin,
J.Kuriyan,
and
A.Weiss
(2009).
The structure, regulation, and function of ZAP-70.
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Immunol Rev,
228,
41-57.
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H.Inaba,
M.Kuboniwa,
B.Bainbridge,
O.Yilmaz,
J.Katz,
K.T.Shiverick,
A.Amano,
and
R.J.Lamont
(2009).
Porphyromonas gingivalis invades human trophoblasts and inhibits proliferation by inducing G1 arrest and apoptosis.
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Cell Microbiol,
11,
1517-1532.
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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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P.J.Day,
A.Cleasby,
I.J.Tickle,
M.O'Reilly,
J.E.Coyle,
F.P.Holding,
R.L.McMenamin,
J.Yon,
R.Chopra,
C.Lengauer,
and
H.Jhoti
(2009).
Crystal structure of human CDK4 in complex with a D-type cyclin.
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Proc Natl Acad Sci U S A,
106,
4166-4170.
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PDB codes:
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Q.Zhong,
N.Simonis,
Q.R.Li,
B.Charloteaux,
F.Heuze,
N.Klitgord,
S.Tam,
H.Yu,
K.Venkatesan,
D.Mou,
V.Swearingen,
M.A.Yildirim,
H.Yan,
A.Dricot,
D.Szeto,
C.Lin,
T.Hao,
C.Fan,
S.Milstein,
D.Dupuy,
R.Brasseur,
D.E.Hill,
M.E.Cusick,
and
M.Vidal
(2009).
Edgetic perturbation models of human inherited disorders.
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Mol Syst Biol,
5,
321.
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R.M.Eglen,
and
T.Reisine
(2009).
The current status of drug discovery against the human kinome.
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Assay Drug Dev Technol,
7,
22-43.
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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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T.Takaki,
A.Echalier,
N.R.Brown,
T.Hunt,
J.A.Endicott,
and
M.E.Noble
(2009).
The structure of CDK4/cyclin D3 has implications for models of CDK activation.
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Proc Natl Acad Sci U S A,
106,
4171-4176.
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PDB code:
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A.A.Michels,
and
O.Bensaude
(2008).
RNA-driven cyclin-dependent kinase regulation: when CDK9/cyclin T subunits of P-TEFb meet their ribonucleoprotein partners.
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Biotechnol J,
3,
1022-1032.
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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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L.Gilles,
R.Guièze,
D.Bluteau,
V.Cordette-Lagarde,
C.Lacout,
R.Favier,
F.Larbret,
N.Debili,
W.Vainchenker,
and
H.Raslova
(2008).
P19INK4D links endomitotic arrest and megakaryocyte maturation and is regulated by AML-1.
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Blood,
111,
4081-4091.
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M.D.Jacobs,
P.R.Caron,
and
B.J.Hare
(2008).
Classifying protein kinase structures guides use of ligand-selectivity profiles to predict inactive conformations: structure of lck/imatinib complex.
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Proteins,
70,
1451-1460.
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PDB code:
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S.Loeper,
and
S.Ezzat
(2008).
Acromegaly: re-thinking the cancer risk.
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Rev Endocr Metab Disord,
9,
41-58.
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Z.Wang,
Y.Xie,
L.Zhang,
H.Zhang,
X.An,
T.Wang,
and
A.Meng
(2008).
Migratory localization of cyclin D2-Cdk4 complex suggests a spatial regulation of the G1-S transition.
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Cell Struct Funct,
33,
171-183.
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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.
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Structure,
15,
625-636.
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PDB code:
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B.Hao,
S.Oehlmann,
M.E.Sowa,
J.W.Harper,
and
N.P.Pavletich
(2007).
Structure of a Fbw7-Skp1-cyclin E complex: multisite-phosphorylated substrate recognition by SCF ubiquitin ligases.
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Mol Cell,
26,
131-143.
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PDB codes:
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S.Donthamsetty,
V.S.Bhave,
M.S.Mitra,
J.R.Latendresse,
and
H.M.Mehendale
(2007).
Nonalcoholic fatty liver sensitizes rats to carbon tetrachloride hepatotoxicity.
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Hepatology,
45,
391-403.
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W.Xu,
X.Yuan,
K.Beebe,
Z.Xiang,
and
L.Neckers
(2007).
Loss of Hsp90 association up-regulates Src-dependent ErbB2 activity.
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Mol Cell Biol,
27,
220-228.
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Y.Kotake,
R.Cao,
P.Viatour,
J.Sage,
Y.Zhang,
and
Y.Xiong
(2007).
pRB family proteins are required for H3K27 trimethylation and Polycomb repression complexes binding to and silencing p16INK4alpha tumor suppressor gene.
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Genes Dev,
21,
49-54.
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A.Ishiguro,
T.Takahata,
M.Saito,
G.Yoshiya,
Y.Tamura,
M.Sasaki,
and
A.Munakata
(2006).
Influence of methylated p15 and p16 genes on clinicopathological features in colorectal cancer.
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J Gastroenterol Hepatol,
21,
1334-1339.
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J.Sridhar,
N.Akula,
and
N.Pattabiraman
(2006).
Selectivity and potency of cyclin-dependent kinase inhibitors.
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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.
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Oncogene,
25,
1620-1628.
|
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K.Terasawa,
K.Yoshimatsu,
S.Iemura,
T.Natsume,
K.Tanaka,
and
Y.Minami
(2006).
Cdc37 interacts with the glycine-rich loop of Hsp90 client kinases.
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Mol Cell Biol,
26,
3378-3389.
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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.
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Structure,
13,
1131-1141.
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PDB code:
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B.Hao,
N.Zheng,
B.A.Schulman,
G.Wu,
J.J.Miller,
M.Pagano,
and
N.P.Pavletich
(2005).
Structural basis of the Cks1-dependent recognition of p27(Kip1) by the SCF(Skp2) ubiquitin ligase.
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Mol Cell,
20,
9.
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PDB codes:
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L.H.Pearl
(2005).
Hsp90 and Cdc37 -- a chaperone cancer conspiracy.
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Curr Opin Genet Dev,
15,
55-61.
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S.M.Rubin,
A.L.Gall,
N.Zheng,
and
N.P.Pavletich
(2005).
Structure of the Rb C-terminal domain bound to E2F1-DP1: a mechanism for phosphorylation-induced E2F release.
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Cell,
123,
1093-1106.
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PDB code:
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X.H.Pei,
and
Y.Xiong
(2005).
Biochemical and cellular mechanisms of mammalian CDK inhibitors: a few unresolved issues.
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Oncogene,
24,
2787-2795.
|
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A.A.Michels,
A.Fraldi,
Q.Li,
T.E.Adamson,
F.Bonnet,
V.T.Nguyen,
S.C.Sedore,
J.P.Price,
D.H.Price,
L.Lania,
and
O.Bensaude
(2004).
Binding of the 7SK snRNA turns the HEXIM1 protein into a P-TEFb (CDK9/cyclin T) inhibitor.
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EMBO J,
23,
2608-2619.
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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.
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Proteins,
55,
214-217.
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PDB code:
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T.Honma
(2003).
Recent advances in de novo design strategy for practical lead identification.
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Med Res Rev,
23,
606-632.
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T.Watanabe,
M.Sugaya,
A.M.Atkins,
E.A.Aquilino,
A.Yang,
D.L.Borris,
J.Brady,
and
A.Blauvelt
(2003).
Kaposi's sarcoma-associated herpesvirus latency-associated nuclear antigen prolongs the life span of primary human umbilical vein endothelial cells.
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J Virol,
77,
6188-6196.
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E.W.Verschuren,
J.Klefstrom,
G.I.Evan,
and
N.Jones
(2002).
The oncogenic potential of Kaposi's sarcoma-associated herpesvirus cyclin is exposed by p53 loss in vitro and in vivo.
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Cancer Cell,
2,
229-241.
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J.Li,
and
M.D.Tsai
(2002).
Novel insights into the INK4-CDK4/6-Rb pathway: counter action of gankyrin against INK4 proteins regulates the CDK4-mediated phosphorylation of Rb.
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Biochemistry,
41,
3977-3983.
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U.Schulze-Gahmen,
and
S.H.Kim
(2002).
Structural basis for CDK6 activation by a virus-encoded cyclin.
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Nat Struct Biol,
9,
177-181.
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PDB code:
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J.Gump,
and
J.Koh
(2001).
An antibody to p16INK4A recognizes a modified form of galectin-3.
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Hybridoma,
20,
167-174.
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P.Kaldis,
P.M.Ojala,
L.Tong,
T.P.Mäkelä,
and
M.J.Solomon
(2001).
CAK-independent activation of CDK6 by a viral cyclin.
|
| |
Mol Biol Cell,
12,
3987-3999.
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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
codes are
shown on the right.
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Links
