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PDBsum entry 2x1n

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protein ligands Protein-protein interface(s) links
Cell cycle PDB id
2x1n
Jmol
Contents
Protein chains
296 a.a. *
258 a.a. *
Ligands
ACE-LEU-ASN-PFF-
NH2
X1N ×2
Waters ×86
* Residue conservation analysis
PDB id:
2x1n
Name: Cell cycle
Title: Truncation and optimisation of peptide inhibitors of cdk2, cyclin a through structure guided design
Structure: Cell division protein kinase 2. Chain: a, c. Synonym: cyclin-dependent kinase 2, p33 protein kinase. Engineered: yes. Cyclin-a2. Chain: b, d. Fragment: residues 172-432. Synonym: cyclin-a. Engineered: yes.
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes
Resolution:
2.75Å     R-factor:   0.201     R-free:   0.254
Authors: G.Kontopidis,M.J.Andrews,C.Mcinnes,A.Plater,L.Innes, S.Renachowski,A.Cowan,P.M.Fischer,N.A.Mcintyre, G.Griffiths,A.L.Barnett,A.M.Z.Slawin,W.Jackson, M.Thomas,D.I.Zheleva,S.Wang,D.G.Blake,N.J.Westwood
Key ref: N.A.McIntyre et al. (2010). Design, synthesis, and evaluation of 2-methyl- and 2-amino-N-aryl-4,5-dihydrothiazolo[4,5-h]quinazolin-8-amines as ring-constrained 2-anilino-4-(thiazol-5-yl)pyrimidine cyclin-dependent kinase inhibitors. J Med Chem, 53, 2136-2145. PubMed id: 20146435 DOI: 10.1021/jm901660c
Date:
31-Dec-09     Release date:   16-Feb-10    
Supersedes: 2wha
PROCHECK
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 Headers
 References

Protein chains
Pfam   ArchSchema ?
P24941  (CDK2_HUMAN) -  Cyclin-dependent kinase 2
Seq:
Struc:
298 a.a.
296 a.a.
Protein chains
Pfam   ArchSchema ?
P20248  (CCNA2_HUMAN) -  Cyclin-A2
Seq:
Struc:
432 a.a.
258 a.a.
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain

 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    
 
 
DOI no: 10.1021/jm901660c J Med Chem 53:2136-2145 (2010)
PubMed id: 20146435  
 
 
Design, synthesis, and evaluation of 2-methyl- and 2-amino-N-aryl-4,5-dihydrothiazolo[4,5-h]quinazolin-8-amines as ring-constrained 2-anilino-4-(thiazol-5-yl)pyrimidine cyclin-dependent kinase inhibitors.
N.A.McIntyre, C.McInnes, G.Griffiths, A.L.Barnett, G.Kontopidis, A.M.Slawin, W.Jackson, M.Thomas, D.I.Zheleva, S.Wang, D.G.Blake, N.J.Westwood, P.M.Fischer.
 
  ABSTRACT  
 
Following the recent discovery and development of 2-anilino-4-(thiazol-5-yl)pyrimidine cyclin dependent kinase (CDK) inhibitors, a program was initiated to evaluate related ring-constrained analogues, specifically, 2-methyl- and 2-amino-N-aryl-4,5-dihydrothiazolo[4,5-h]quinazolin-8-amines for inhibition of CDKs. Here we report the rational design, synthesis, structure-activity relationships (SARs), and cellular mode-of-action profile of these second generation CDK inhibitors. Many of the analogues from this chemical series inhibit CDKs with very low nanomolar K(i) values. The most potent compound reported in this study inhibits CDK2 with an IC(50) of 0.7 nM ([ATP] = 100 microM). Furthermore, an X-ray crystal structure of 2-methyl-N-(3-(nitro)phenyl)-4,5-dihydrothiazolo[4,5-h]quinazolin-8-amine (11g), a representative from the chemical series in complex with cyclin A-CDK2, is reported, confirming the design rationale and expected binding mode within the CDK2 ATP binding pocket.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21286784 P.Dobeš, J.Fanfrlík, J.Rezáč, M.Otyepka, and P.Hobza (2011).
Transferable scoring function based on semiempirical quantum mechanical PM6-DH2 method: CDK2 with 15 structurally diverse inhibitors.
  J Comput Aided Mol Des, 25, 223-235.  
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