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PDBsum entry 4eol

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protein ligands metals Protein-protein interface(s) links
Transferase/transferase inhibitor PDB id
4eol
Jmol
Contents
Protein chains
295 a.a.
257 a.a.
Ligands
1RO ×2
SGM ×2
Metals
_MG
Waters ×66
PDB id:
4eol
Name: Transferase/transferase inhibitor
Title: Thr 160 phosphorylated cdk2 h84s, q85m, k89d - human cyclin with the inhibitor ro3306
Structure: Cyclin-dependent kinase 2. Chain: a, c. Synonym: cell division protein kinase 2, p33 protein kinase engineered: yes. Mutation: yes. Cyclin-a2. Chain: b, d. Fragment: c-terminal fragment. Synonym: cyclin-a.
Source: 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
Resolution:
2.40Å     R-factor:   0.220     R-free:   0.246
Authors: A.Echalier,E.Cot,A.Camasses,E.Hodimont,F.Hoh,F.Sheinerman, L.Krasinska,D.Fisher
Key ref: 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: 22921070
Date:
14-Apr-12     Release date:   06-Feb-13    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P24941  (CDK2_HUMAN) -  Cyclin-dependent kinase 2
Seq:
Struc:
298 a.a.
295 a.a.*
Protein chains
Pfam   ArchSchema ?
P20248  (CCNA2_HUMAN) -  Cyclin-A2
Seq:
Struc:
432 a.a.
257 a.a.
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 4 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: Chains A, C: E.C.2.7.11.22  - Cyclin-dependent kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + a protein = ADP + a phosphoprotein
ATP
+ protein
= ADP
+ phosphoprotein
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     cyclin-dependent protein kinase holoenzyme complex   15 terms 
  Biological process     regulation of gene silencing   30 terms 
  Biochemical function     nucleotide binding     13 terms  

 

 
    reference    
 
 
Chem Biol 19:1028-1040 (2012)
PubMed id: 22921070  
 
 
An integrated chemical biology approach provides insight into Cdk2 functional redundancy and inhibitor sensitivity.
A.Echalier, E.Cot, A.Camasses, E.Hodimont, F.Hoh, P.Jay, F.Sheinerman, L.Krasinska, D.Fisher.
 
  ABSTRACT  
 
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.