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PDBsum entry 3fqh

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protein ligands Protein-protein interface(s) links
Transferase PDB id
3fqh
Jmol
Contents
Protein chains
262 a.a. *
Ligands
057 ×2
Waters ×108
* Residue conservation analysis
PDB id:
3fqh
Name: Transferase
Title: Crystal structure of spleen tyrosine kinase complexed with a 2-substituted 7-azaindole
Structure: Tyrosine-protein kinase syk. Chain: a, b. Fragment: unp residues 365-635, protein kinase domain. Synonym: spleen tyrosine kinase. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: syk. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf9.
Resolution:
2.26Å     R-factor:   0.216     R-free:   0.259
Authors: A.Kuglstatter,A.G.Villasenor
Key ref: A.G.Villaseñor et al. (2009). Structural insights for design of potent spleen tyrosine kinase inhibitors from crystallographic analysis of three inhibitor complexes. Chem Biol Drug Des, 73, 466-470. PubMed id: 19220318
Date:
07-Jan-09     Release date:   10-Mar-09    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P43405  (KSYK_HUMAN) -  Tyrosine-protein kinase SYK
Seq:
Struc:
 
Seq:
Struc:
635 a.a.
262 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
+ [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     transferase activity, transferring phosphorus-containing groups     4 terms  

 

 
    reference    
 
 
Chem Biol Drug Des 73:466-470 (2009)
PubMed id: 19220318  
 
 
Structural insights for design of potent spleen tyrosine kinase inhibitors from crystallographic analysis of three inhibitor complexes.
A.G.Villaseñor, R.Kondru, H.Ho, S.Wang, E.Papp, D.Shaw, J.W.Barnett, M.F.Browner, A.Kuglstatter.
 
  ABSTRACT  
 
Spleen tyrosine kinase is considered an attractive drug target for the treatment of allergic and antibody mediated autoimmune diseases. We have determined the co-crystal structures of spleen tyrosine kinase complexed with three known inhibitors: YM193306, a 7-azaindole derivative and R406. The cis-cyclohexyldiamino moiety of YM193306 is forming four hydrophobically shielded polar interactions with the spleen tyrosine kinase protein and is therefore crucial for the high potency of this inhibitor. Its primary amino group is inducing a conformational change of the spleen tyrosine kinase DFG Asp side chain. The crystal structure of the 7-azaindole derivative bound to spleen tyrosine kinase is the first demonstration of a 2-substituted 7-azaindole bound to a protein kinase. Its indole-amide substituent is tightly packed between the N- and C-terminal kinase lobes. The co-crystal structure of the spleen tyrosine kinase-R406 complex shows two main differences to the previously reported structure of spleen tyrosine kinase soaked with R406: (i) the side chain of the highly conserved Lys is disordered and not forming a hydrogen bond to R406 and (ii) the DFG Asp side chain is pointing away from and not towards R406. The novel protein-ligand interactions and protein conformational changes revealed in these structures guide the rational design and structure-based optimization of second-generation spleen tyrosine kinase inhibitors.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21280133 A.Kuglstatter, A.Wong, S.Tsing, S.W.Lee, Y.Lou, A.G.Villaseñor, J.M.Bradshaw, D.Shaw, J.W.Barnett, and M.F.Browner (2011).
Insights into the conformational flexibility of Bruton's tyrosine kinase from multiple ligand complex structures.
  Protein Sci, 20, 428-436.
PDB codes: 3pix 3piy 3piz 3pj1 3pj2 3pj3
20836676 F.M.Uckun, and S.Qazi (2010).
Spleen tyrosine kinase as a molecular target for treatment of leukemias and lymphomas.
  Expert Rev Anticancer Ther, 10, 1407-1418.  
19491390 M.P.Quiroga, K.Balakrishnan, A.V.Kurtova, M.Sivina, M.J.Keating, W.G.Wierda, V.Gandhi, and J.A.Burger (2009).
B-cell antigen receptor signaling enhances chronic lymphocytic leukemia cell migration and survival: specific targeting with a novel spleen tyrosine kinase inhibitor, R406.
  Blood, 114, 1029-1037.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.