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PDBsum entry 3el8

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protein ligands Protein-protein interface(s) links
Transferase PDB id
3el8
Jmol
Contents
Protein chains
263 a.a. *
Ligands
PD5
Waters ×176
* Residue conservation analysis
PDB id:
3el8
Name: Transferase
Title: Crystal structure of c-src in complex with pyrazolopyrimidin
Structure: Proto-oncogene tyrosine-protein kinase src. Chain: a, b. Fragment: protein kinase domain: unp residues 251-533. Synonym: p60-src, c-src, pp60c-src. Engineered: yes
Source: Gallus gallus. Chicken. Organism_taxid: 9031. Gene: src. Expressed in: escherichia coli.
Resolution:
2.30Å     R-factor:   0.218     R-free:   0.262
Authors: A.C.Dar,M.S.Lopez,K.M.Shokat
Key ref: A.C.Dar et al. (2008). Small molecule recognition of c-Src via the Imatinib-binding conformation. Chem Biol, 15, 1015-1022. PubMed id: 18940662
Date:
20-Sep-08     Release date:   28-Oct-08    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P00523  (SRC_CHICK) -  Proto-oncogene tyrosine-protein kinase Src
Seq:
Struc:
 
Seq:
Struc:
533 a.a.
263 a.a.
Key:    PfamA domain  PfamB 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 15:1015-1022 (2008)
PubMed id: 18940662  
 
 
Small molecule recognition of c-Src via the Imatinib-binding conformation.
A.C.Dar, M.S.Lopez, K.M.Shokat.
 
  ABSTRACT  
 
The cancer drug, Imatinib, is a selective Abl kinase inhibitor that does not inhibit the closely related kinase c-Src. This one drug and its ability to selectively inhibit Abl over c-Src has been a guiding principle in virtually all kinase drug discovery efforts in the last 15 years. A prominent hypothesis explaining the selectivity of Imatinib is that Abl has an intrinsic ability to adopt an inactive conformation (termed DFG-out), whereas c-Src appears to pay a high intrinsic energetic penalty for adopting this conformation, effectively excluding Imatinib from its ATP pocket. This explanation of the difference in binding affinity of Imatinib for Abl versus c-Src makes the striking prediction that it would not be possible to design an inhibitor that binds to the DFG-out conformation of c-Src with high affinity. We report the discovery of a series of such inhibitors. We use structure-activity relationships and X-ray crystallography to confirm our findings. These studies suggest that small molecules are capable of inducing the generally unfavorable DFG-out conformation in c-Src. Structural comparison between c-Src in complex with these inhibitors allows us to speculate on the differential selectivity of Imatinib for c-Src and Abl.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
22678283 A.C.Dar, T.K.Das, K.M.Shokat, and R.L.Cagan (2012).
Chemical genetic discovery of targets and anti-targets for cancer polypharmacology.
  Nature, 486, 80-84.  
20067443 C.A.Dodson, M.Kosmopoulou, M.W.Richards, B.Atrash, V.Bavetsias, J.Blagg, and R.Bayliss (2010).
Crystal structure of an Aurora-A mutant that mimics Aurora-B bound to MLN8054: insights into selectivity and drug design.
  Biochem J, 427, 19-28.
PDB codes: 2wtv 2wtw
20189109 P.Ranjitkar, A.M.Brock, and D.J.Maly (2010).
Affinity reagents that target a specific inactive form of protein kinases.
  Chem Biol, 17, 195-206.  
19895503 T.Zhou, L.Commodore, W.S.Huang, Y.Wang, T.K.Sawyer, W.C.Shakespeare, T.Clackson, X.Zhu, and D.C.Dalgarno (2010).
Structural analysis of DFG-in and DFG-out dual Src-Abl inhibitors sharing a common vinyl purine template.
  Chem Biol Drug Des, 75, 18-28.
PDB codes: 3kf4 3kfa
19396179 J.R.Simard, S.Klüter, C.Grütter, M.Getlik, M.Rabiller, H.B.Rode, and D.Rauh (2009).
A new screening assay for allosteric inhibitors of cSrc.
  Nat Chem Biol, 5, 394-396.
PDB codes: 3f3t 3f3u
19675896 M.Klein, P.Dinér, D.Dorin-Semblat, C.Doerig, and M.Grøtli (2009).
Synthesis of 3-(1,2,3-triazol-1-yl)- and 3-(1,2,3-triazol-4-yl)-substituted pyrazolo[3,4-d]pyrimidin-4-amines via click chemistry: potential inhibitors of the Plasmodium falciparum PfPK7 protein kinase.
  Org Biomol Chem, 7, 3421-3429.  
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.