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PDBsum entry 4bcg

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protein ligands Protein-protein interface(s) links
Transferase/cell cycle PDB id
4bcg
Jmol
Contents
Protein chains
313 a.a.
252 a.a.
Ligands
T3C
GOL ×2
Waters ×16
PDB id:
4bcg
Name: Transferase/cell cycle
Title: Structure of cdk9 in complex with cyclin t and a 2-amino-4- heteroaryl-pyrimidine inhibitor
Structure: Cyclin-dependent kinase 9. Chain: a. Fragment: residues 2-330. Synonym: c-2k, cell division cycle 2-like protein kinase 4, division protein kinase 9, serine/threonine-protein kinase pitalre, tat-associated kinase complex catalytic subunit. Engineered: yes. Cyclin-t1. Chain: b.
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108.
Resolution:
3.08Å     R-factor:   0.163     R-free:   0.197
Authors: A.J.Hole,S.Baumli,S.Wang,J.A.Endicott,M.E.M.Noble
Key ref: H.Shao et al. (2013). Substituted 4-(thiazol-5-yl)-2-(phenylamino)pyrimidines are highly active CDK9 inhibitors: synthesis, X-ray crystal structures, structure-activity relationship, and anticancer activities. J Med Chem, 56, 640-659. PubMed id: 23301767
Date:
02-Oct-12     Release date:   17-Apr-13    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P50750  (CDK9_HUMAN) -  Cyclin-dependent kinase 9
Seq:
Struc:
372 a.a.
313 a.a.*
Protein chain
Pfam   ArchSchema ?
O60563  (CCNT1_HUMAN) -  Cyclin-T1
Seq:
Struc:
 
Seq:
Struc:
726 a.a.
252 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 2: Chain A: E.C.2.7.11.22  - Cyclin-dependent kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + a protein = ADP + a phosphoprotein
ATP
+ protein
= ADP
+ phosphoprotein
   Enzyme class 3: Chain A: E.C.2.7.11.23  - [RNA-polymerase]-subunit kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + [DNA-directed RNA polymerase] = ADP + [DNA-directed RNA polymerase] phosphate
ATP
+ [DNA-directed RNA polymerase]
= ADP
+ [DNA-directed RNA polymerase] phosphate
Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     transcription, DNA-dependent   4 terms 
  Biochemical function     transferase activity, transferring phosphorus-containing groups     5 terms  

 

 
    reference    
 
 
J Med Chem 56:640-659 (2013)
PubMed id: 23301767  
 
 
Substituted 4-(thiazol-5-yl)-2-(phenylamino)pyrimidines are highly active CDK9 inhibitors: synthesis, X-ray crystal structures, structure-activity relationship, and anticancer activities.
H.Shao, S.Shi, S.Huang, A.J.Hole, A.Y.Abbas, S.Baumli, X.Liu, F.Lam, D.W.Foley, P.M.Fischer, M.Noble, J.A.Endicott, C.Pepper, S.Wang.
 
  ABSTRACT  
 
Cancer cells often have a high demand for antiapoptotic proteins in order to resist programmed cell death. CDK9 inhibition selectively targets survival proteins and reinstates apoptosis in cancer cells. We designed a series of 4-thiazol-2-anilinopyrimidine derivatives with functional groups attached to the C5-position of the pyrimidine or to the C4-thiazol moiety and investigated their effects on CDK9 potency and selectivity. One of the most selective compounds, 12u inhibits CDK9 with IC(50) = 7 nM and shows over 80-fold selectivity for CDK9 versus CDK2. X-ray crystal structures of 12u bound to CDK9 and CDK2 provide insights into the binding modes. This work, together with crystal structures of selected inhibitors in complex with both enzymes described in a companion paper, (34) provides a rationale for the observed SAR. 12u demonstrates potent anticancer activity against primary chronic lymphocytic leukemia cells with a therapeutic window 31- and 107-fold over those of normal B- and T-cells.