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PDBsum entry 3g6h

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protein ligands Protein-protein interface(s) links
Transferase PDB id
3g6h
Jmol
Contents
Protein chains
266 a.a. *
Ligands
G6H
Waters ×113
* Residue conservation analysis
PDB id:
3g6h
Name: Transferase
Title: Src thr338ile inhibited in the dfg-asp-out conformation
Structure: Proto-oncogene tyrosine-protein kinase src. Chain: a, b. Fragment: protein kinase domain. Synonym: pp60c-src, p60-src, c-src. Engineered: yes. Mutation: yes
Source: Gallus gallus. Chicken. Organism_taxid: 9031. Gene: src. Expressed in: escherichia coli. Expression_system_taxid: 562.
Resolution:
2.35Å     R-factor:   0.228     R-free:   0.283
Authors: M.A.Seeliger,P.Ranjitkar,C.Kasap,Y.Shan,D.E.Shaw,N.P.Shah, J.Kuriyan,D.J.Maly
Key ref: M.A.Seeliger et al. (2009). Equally potent inhibition of c-Src and Abl by compounds that recognize inactive kinase conformations. Cancer Res, 69, 2384-2392. PubMed id: 19276351 DOI: 10.1158/0008-5472.CAN-08-3953
Date:
06-Feb-09     Release date:   24-Mar-09    
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.
266 a.a.*
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 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     regulation of signal transduction   2 terms 
  Biochemical function     transferase activity, transferring phosphorus-containing groups     5 terms  

 

 
    reference    
 
 
DOI no: 10.1158/0008-5472.CAN-08-3953 Cancer Res 69:2384-2392 (2009)
PubMed id: 19276351  
 
 
Equally potent inhibition of c-Src and Abl by compounds that recognize inactive kinase conformations.
M.A.Seeliger, P.Ranjitkar, C.Kasap, Y.Shan, D.E.Shaw, N.P.Shah, J.Kuriyan, D.J.Maly.
 
  ABSTRACT  
 
Imatinib is an inhibitor of the Abl tyrosine kinase domain that is effective in the treatment of chronic myelogenic leukemia. Although imatinib binds tightly to the Abl kinase domain, its affinity for the closely related kinase domain of c-Src is at least 2,000-fold lower. Imatinib recognition requires a specific inactive conformation of the kinase domain, in which a conserved Asp-Phe-Gly (DFG) motif is flipped with respect to the active conformation. The inability of c-Src to readily adopt this flipped DFG conformation was thought to underlie the selectivity of imatinib for Abl over c-Src. Here, we present a series of inhibitors (DSA compounds) that are based on the core scaffold of imatinib but which bind with equally high potency to c-Src and Abl. The DSA compounds bind to c-Src in the DFG-flipped conformation, as confirmed by crystal structures and kinetic analysis. The origin of the high affinity of these compounds for c-Src is suggested by the fact that they also inhibit clinically relevant Abl variants bearing mutations in a structural element, the P-loop, that normally interacts with the phosphate groups of ATP but is folded over a substructure of imatinib in Abl. Importantly, several of the DSA compounds block the growth of Ba/F3 cells harboring imatinib-resistant BCR-ABL mutants, including the Thr315Ile "gatekeeper" mutation, but do not suppress the growth of parental Ba/F3 cells.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21474065 N.Jura, X.Zhang, N.F.Endres, M.A.Seeliger, T.Schindler, and J.Kuriyan (2011).
Catalytic control in the EGF receptor and its connection to general kinase regulatory mechanisms.
  Mol Cell, 42, 9.  
21264348 R.E.Iacob, J.Zhang, N.S.Gray, and J.R.Engen (2011).
Allosteric interactions between the myristate- and ATP-site of the Abl kinase.
  PLoS One, 6, e15929.  
21060940 Z.B.Hill, B.G.Perera, and D.J.Maly (2011).
Bivalent inhibitors of the tyrosine kinases ABL and SRC: determinants of potency and selectivity.
  Mol Biosyst, 7, 447-456.  
20060708 B.J.Grant, A.A.Gorfe, and J.A.McCammon (2010).
Large conformational changes in proteins: signaling and other functions.
  Curr Opin Struct Biol, 20, 142-147.  
20299508 E.Weisberg, H.G.Choi, A.Ray, R.Barrett, J.Zhang, T.Sim, W.Zhou, M.Seeliger, M.Cameron, M.Azam, J.A.Fletcher, M.Debiec-Rychter, M.Mayeda, D.Moreno, A.L.Kung, P.A.Janne, R.Khosravi-Far, J.V.Melo, P.W.Manley, S.Adamia, C.Wu, N.Gray, and J.D.Griffin (2010).
Discovery of a small-molecule type II inhibitor of wild-type and gatekeeper mutants of BCR-ABL, PDGFRalpha, Kit, and Src kinases: novel type II inhibitor of gatekeeper mutants.
  Blood, 115, 4206-4216.
PDB code: 4agw
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.  
  20044834 R.Krishnamurty, and D.J.Maly (2010).
Biochemical mechanisms of resistance to small-molecule protein kinase inhibitors.
  ACS Chem Biol, 5, 121-138.  
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
19714203 A.Dixit, and G.M.Verkhivker (2009).
Hierarchical modeling of activation mechanisms in the ABL and EGFR kinase domains: thermodynamic and mechanistic catalysts of kinase activation by cancer mutations.
  PLoS Comput Biol, 5, e1000487.  
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 code is shown on the right.