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PDBsum entry 4gu9

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protein ligands Protein-protein interface(s) links
Transferase PDB id
4gu9
Jmol PyMol
Contents
Protein chains
252 a.a.
Ligands
4GU ×2
Waters ×133
PDB id:
4gu9
Name: Transferase
Title: Focal adhesion kinase catalytic domain in complex with (2-fl phenyl)-(1h-pyrazolo[3,4-d]pyrimidin-4-yl)-amine
Structure: Focal adhesion kinase 1. Chain: a, b. Fragment: catalytic protein kinase domain resides 410-686. Synonym: fadk 1, focal adhesion kinase-related nonkinase, f protein phosphatase 1 regulatory subunit 71, ppp1r71, prote tyrosine kinase 2, p125fak, pp125fak. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: ptk2, fak, fak1. Expressed in: trichoplusia ni. Expression_system_taxid: 7111
Resolution:
2.40Å     R-factor:   0.180     R-free:   0.221
Authors: D.Musil
Key ref: T.Heinrich et al. (2013). Fragment-based discovery of new highly substituted 1H-pyrrolo[2,3-b]- and 3H-imidazolo[4,5-b]-pyridines as focal adhesion kinase inhibitors. J Med Chem, 56, 1160-1170. PubMed id: 23294348
Date:
29-Aug-12     Release date:   04-Sep-13    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
Q05397  (FAK1_HUMAN) -  Focal adhesion kinase 1
Seq:
Struc:
 
Seq:
Struc:
 
Seq:
Struc:
1052 a.a.
252 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.2.7.10.2  - Non-specific protein-tyrosine kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate
ATP
+ [protein]-L-tyrosine
=
ADP
Bound ligand (Het Group name = 4GU)
matches with 41.94% similarity
+ [protein]-L-tyrosine phosphate
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     protein phosphorylation   1 term 
  Biochemical function     protein kinase activity     2 terms  

 

 
    reference    
 
 
J Med Chem 56:1160-1170 (2013)
PubMed id: 23294348  
 
 
Fragment-based discovery of new highly substituted 1H-pyrrolo[2,3-b]- and 3H-imidazolo[4,5-b]-pyridines as focal adhesion kinase inhibitors.
T.Heinrich, J.Seenisamy, L.Emmanuvel, S.S.Kulkarni, J.Bomke, F.Rohdich, H.Greiner, C.Esdar, M.Krier, U.Grädler, D.Musil.
 
  ABSTRACT  
 
Focal adhesion kinase (FAK) is considered as an attractive target for oncology, and small-molecule inhibitors are reported to be in clinical testing. In a surface plasmon resonance (SPR)-mediated fragment screening campaign, we discovered bicyclic scaffolds like 1H-pyrazolo[3,4-d]pyrimidines binding to the hinge region of FAK. By an accelerated knowledge-based fragment growing approach, essential pharmacophores were added. The establishment of highly substituted unprecedented 1H-pyrrolo[2,3-b]pyridine derivatizations provided compounds with submicromolar cellular FAK inhibition potential. The combination of substituents on the bicyclic templates and the nature of the core structure itself have a significant impact on the compounds FAK selectivity. Structural analysis revealed that the appropriately substituted pyrrolo[2,3-b]pyridine induced a rare helical DFG-loop conformation. The discovered synthetic route to introduce three different substituents independently paves the way for versatile applications of the 7-azaindole core.
 

 

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