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PDBsum entry 4eoq
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Transferase, cell cycle
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PDB id
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4eoq
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Contents |
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296 a.a.
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257 a.a.
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276 a.a.
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PDB id:
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| Name: |
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Transferase, cell cycle
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Title:
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Thr 160 phosphorylated cdk2 wt - human cyclin a3 complex with atp
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Structure:
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Cyclin-dependent kinase 2. Chain: a, c. Synonym: cell division protein kinase 2, p33 protein kinase. Engineered: yes. Cyclin-a2. Chain: b, d. Fragment: c-terminal fragment. Synonym: cyclin-a. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: cdk2, cdkn2. Expressed in: escherichia coli. Expression_system_taxid: 562. Gene: ccna2, ccn1, ccna. Expression_system_taxid: 562
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Resolution:
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2.15Å
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R-factor:
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0.201
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R-free:
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0.234
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Authors:
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A.Echalier,E.Cot,A.Camasses,E.Hodimont,F.Hoh,F.Sheinerman, L.Krasinska,D.Fisher
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Key ref:
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A.Echalier
et al.
(2012).
An integrated chemical biology approach provides insight into Cdk2 functional redundancy and inhibitor sensitivity.
Chem Biol,
19,
1028-1040.
PubMed id:
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Date:
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14-Apr-12
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Release date:
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06-Feb-13
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PROCHECK
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Headers
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References
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P24941
(CDK2_HUMAN) -
Cyclin-dependent kinase 2 from Homo sapiens
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Seq:
Struc:
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298 a.a.
296 a.a.*
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Enzyme class:
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Chains A, C:
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]
Bound ligand (Het Group name = )
corresponds exactly
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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]
Bound ligand (Het Group name = )
corresponds exactly
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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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Chem Biol
19:1028-1040
(2012)
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PubMed id:
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An integrated chemical biology approach provides insight into Cdk2 functional redundancy and inhibitor sensitivity.
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A.Echalier,
E.Cot,
A.Camasses,
E.Hodimont,
F.Hoh,
P.Jay,
F.Sheinerman,
L.Krasinska,
D.Fisher.
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ABSTRACT
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Cdk2 promotes DNA replication and is a promising cancer therapeutic target, but
its functions appear redundant with Cdk1, an essential Cdk affected by most Cdk2
inhibitors. Here, we present an integrated multidisciplinary approach to address
Cdk redundancy. Mathematical modeling of enzymology data predicted conditions
allowing selective chemical Cdk2 inhibition. Together with experiments in
Xenopus egg extracts, this supports a rate-limiting role for Cdk2 in DNA
replication. To confirm this we designed inhibitor-resistant (ir)-Cdk2 mutants
using a novel bioinformatics approach. Bypassing inhibition with ir-Cdk2 or with
Cdk1 shows that Cdk2 is rate-limiting for replication in this system because
Cdk1 is insufficiently active. Additionally, crystal structures and kinetics
reveal alternative binding modes of Cdk1-selective and Cdk2-selective inhibitors
and mechanisms of Cdk2 inhibitor resistance. Our approach thus provides insight
into structure, functions, and biochemistry of a cyclin-dependent kinase.
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