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PDBsum entry 4iq6

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protein ligands Protein-protein interface(s) links
Transferase/transferase inhibitor PDB id
4iq6
Jmol
Contents
Protein chains
324 a.a.
Ligands
IQ6 ×2
PDB id:
4iq6
Name: Transferase/transferase inhibitor
Title: Gsk-3beta with inhibitor 6-chloro-n-cyclohexyl-4-(1h-pyrrolo b]pyridin-3-yl)pyridin-2-amine
Structure: Glycogen synthase kinase-3 beta. Chain: a, b. Synonym: gsk-3 beta, serine/threonine-protein kinase gsk3b. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: gsk3b. Expressed in: baculovirus. Expression_system_taxid: 7108.
Resolution:
3.12Å     R-factor:   0.188     R-free:   0.227
Authors: Y.Tong,K.D.Stewart,A.S.Florjancic,J.E.Harlan,P.J.Merta, M.Przytulinska,N.Soni,K.S.Swinger,H.Zhu,E.F.Johnson,A.R.Sho T.D.Penning
Key ref: Y.Tong et al. (2013). Azaindole-Based Inhibitors of Cdc7 Kinase: Impact of the Pre-DFG Residue, Val 195. ACS Med Chem Lett, 4, 211-215. PubMed id: 24900653 DOI: 10.1021/ml300348c
Date:
10-Jan-13     Release date:   24-Apr-13    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P49841  (GSK3B_HUMAN) -  Glycogen synthase kinase-3 beta
Seq:
Struc:
420 a.a.
324 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class 1: E.C.2.7.11.1  - Non-specific serine/threonine protein kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + a protein = ADP + a phosphoprotein
ATP
+ protein
= ADP
+ phosphoprotein
   Enzyme class 2: E.C.2.7.11.26  - [Tau protein] kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + [tau protein] = ADP + [tau protein] phosphate
ATP
+ [tau protein]
= ADP
+ [tau protein] 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!
  Cellular component     cell body   18 terms 
  Biological process     protein localization to microtubule   72 terms 
  Biochemical function     RNA polymerase II transcription factor binding     19 terms  

 

 
    reference    
 
 
DOI no: 10.1021/ml300348c ACS Med Chem Lett 4:211-215 (2013)
PubMed id: 24900653  
 
 
Azaindole-Based Inhibitors of Cdc7 Kinase: Impact of the Pre-DFG Residue, Val 195.
Y.Tong, K.D.Stewart, A.S.Florjancic, J.E.Harlan, P.J.Merta, M.Przytulinska, N.Soni, K.K.Swinger, H.Zhu, E.F.Johnson, A.R.Shoemaker, T.D.Penning.
 
  ABSTRACT  
 
To investigate the role played by the unique pre-DFG residue Val 195 of Cdc7 kinase on the potency of azaindole-chloropyridines (1), a series of novel analogues with various chloro replacements were synthesized and evaluated for their inhibitory activity against Cdc7. X-ray cocrystallization using a surrogate protein, GSK3β, and modeling studies confirmed the azaindole motif as the hinge binder. Weaker hydrophobic interactions with Met 134 and Val 195 by certain chloro replacements (e.g., H, methyl) led to reduced Cdc7 inhibition. Meanwhile, data from other replacements (e.g., F, O) indicated that loss of such hydrophobic interaction could be compensated by enhanced hydrogen bonding to Lys 90. Our findings not only provide an in-depth understanding of the pre-DFG residue as another viable position impacting kinase inhibition, they also expand the existing knowledge of ligand-Cdc7 binding.