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PDBsum entry 4bcf

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protein ligands Protein-protein interface(s) links
Transferase/cell cycle PDB id
4bcf
Jmol
Contents
Protein chains
308 a.a.
252 a.a.
Ligands
T6Q
Waters ×14
PDB id:
4bcf
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:
3.01Å     R-factor:   0.169     R-free:   0.224
Authors: A.J.Hole,S.Baumli,S.Wang,J.A.Endicott,M.E.M.Noble
Key ref: A.J.Hole et al. (2013). Comparative structural and functional studies of 4-(thiazol-5-yl)-2-(phenylamino)pyrimidine-5-carbonitrile CDK9 inhibitors suggest the basis for isotype selectivity. J Med Chem, 56, 660-670. PubMed id: 23252711 DOI: 10.1021/jm301495v
Date:
02-Oct-12     Release date:   09-Jan-13    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P50750  (CDK9_HUMAN) -  Cyclin-dependent kinase 9
Seq:
Struc:
372 a.a.
308 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    
 
 
DOI no: 10.1021/jm301495v J Med Chem 56:660-670 (2013)
PubMed id: 23252711  
 
 
Comparative structural and functional studies of 4-(thiazol-5-yl)-2-(phenylamino)pyrimidine-5-carbonitrile CDK9 inhibitors suggest the basis for isotype selectivity.
A.J.Hole, S.Baumli, H.Shao, S.Shi, S.Huang, C.Pepper, P.M.Fischer, S.Wang, J.A.Endicott, M.E.Noble.
 
  ABSTRACT  
 
Cyclin-dependent kinase 9/cyclin T, the protein kinase heterodimer that constitutes positive transcription elongation factor b, is a well-validated target for treatment of several diseases, including cancer and cardiac hypertrophy. In order to aid inhibitor design and rationalize the basis for CDK9 selectivity, we have studied the CDK-binding properties of six different members of a 4-(thiazol-5-yl)-2-(phenylamino)pyrimidine-5-carbonitrile series that bind to both CDK9/cyclin T and CDK2/cyclin A. We find that for a given CDK, the melting temperature of a CDK/cyclin/inhibitor complex correlates well with inhibitor potency, suggesting that differential scanning fluorimetry (DSF) is a useful orthogonal measure of inhibitory activity for this series. We have used DSF to demonstrate that the binding of these compounds is independent of the presence or absence of the C-terminal tail region of CDK9, unlike the binding of the CDK9-selective inhibitor 5,6-dichlorobenzimidazone-1-β-d-ribofuranoside (DRB). Finally, on the basis of 11 cocrystal structures bound to CDK9/cyclin T or CDK2/cyclin A, we conclude that selective inhibition of CDK9/cyclin T by members of the 4-(thiazol-5-yl)-2-(phenylamino)pyrimidine-5-carbonitrile series results from the relative malleability of the CDK9 active site rather than from the formation of specific polar contacts.