PDBsum entry 3bkb

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protein ligands links
Transferase PDB id
Jmol PyMol
Protein chain
373 a.a. *
SO4 ×3
EDO ×8
Waters ×389
* Residue conservation analysis
PDB id:
Name: Transferase
Title: Crystal structure of human feline sarcoma viral oncogene hom fes)
Structure: Proto-oncogene tyrosine-protein kinase fes/fps. Chain: a. Fragment: residues 448-822. Synonym: c-fes. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: fes, fps. Expressed in: escherichia coli. Expression_system_taxid: 562.
1.78Å     R-factor:   0.150     R-free:   0.189
Authors: P.Filippakopoulos,E.Salah,O.Fedorov,C.Cooper,E.Ugochukwu,A.C F.Von Delft,C.H.Arrowsmith,A.M.Edwards,J.Weigelt,S.Knapp,St Genomics Consortium (Sgc)
Key ref:
P.Filippakopoulos et al. (2008). Structural coupling of SH2-kinase domains links Fes and Abl substrate recognition and kinase activation. Cell, 134, 793-803. PubMed id: 18775312 DOI: 10.1016/j.cell.2008.07.047
06-Dec-07     Release date:   25-Dec-07    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P07332  (FES_HUMAN) -  Tyrosine-protein kinase Fes/Fps
822 a.a.
373 a.a.
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.  - Non-specific protein-tyrosine kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate
+ [protein]-L-tyrosine
+ [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  


DOI no: 10.1016/j.cell.2008.07.047 Cell 134:793-803 (2008)
PubMed id: 18775312  
Structural coupling of SH2-kinase domains links Fes and Abl substrate recognition and kinase activation.
P.Filippakopoulos, M.Kofler, O.Hantschel, G.D.Gish, F.Grebien, E.Salah, P.Neudecker, L.E.Kay, B.E.Turk, G.Superti-Furga, T.Pawson, S.Knapp.
The SH2 domain of cytoplasmic tyrosine kinases can enhance catalytic activity and substrate recognition, but the molecular mechanisms by which this is achieved are poorly understood. We have solved the structure of the prototypic SH2-kinase unit of the human Fes tyrosine kinase, which appears specialized for positive signaling. In its active conformation, the SH2 domain tightly interacts with the kinase N-terminal lobe and positions the kinase alphaC helix in an active configuration through essential packing and electrostatic interactions. This interaction is stabilized by ligand binding to the SH2 domain. Our data indicate that Fes kinase activation is closely coupled to substrate recognition through cooperative SH2-kinase-substrate interactions. Similarly, we find that the SH2 domain of the active Abl kinase stimulates catalytic activity and substrate phosphorylation through a distinct SH2-kinase interface. Thus, the SH2 and catalytic domains of active Fes and Abl pro-oncogenic kinases form integrated structures essential for effective tyrosine kinase signaling.
  Selected figure(s)  
Figure 4.
Substrate Interaction with the Fes Kinase Domain (A) Details of the substrate peptide (IYESL) interaction with the kinase domain. (B) Structure of the Fes-substrate complex showing a detail of the location of the peptide (shown in sticks). The surface has been colored by electrostatic potential between [minus sign]10 and +10 kcal/mol. (C) 2F[o] -- F[c] electron density map contoured at 2[sigma] around the substrate peptide residues. Cell. 2008 September 5; 134(5): 793–803. doi: 10.1016/j.cell.2008.07.047. Copyright [copyright] 2008 ELL & Excerpta Medica
Figure 7.
Cartoon Representation of Fes Activation In its unligated and unphosphorylated state, the Fes SH2 domain (blue), [alpha]C (red), and activation segment (purple) are significantly disordered (left). Binding of a primed peptide (yellow) stabilizes the SH2 domain, leading to a productive orientation of the SH2 domain, with respect to the kinase domain, and stable positioning of [alpha]C (middle). Phosphorylation of the activation segment at Y713 and binding of the substrate molecule to the kinase domain stabilizes the activation segment in a conformation suitable for catalysis (right). Cell. 2008 September 5; 134(5): 793–803. doi: 10.1016/j.cell.2008.07.047. Copyright [copyright] 2008 ELL & Excerpta Medica
  The above figures are reprinted from an Open Access publication published by Cell Press: Cell (2008, 134, 793-803) copyright 2008.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21199370 B.R.Groveman, S.Xue, V.Marin, J.Xu, M.K.Ali, E.A.Bienkiewicz, and X.M.Yu (2011).
Roles of the SH2 and SH3 domains in the regulation of neuronal Src kinase functions.
  FEBS J, 278, 643-653.  
21320496 M.Sato, M.Maruoka, N.Yokota, M.Kuwano, A.Matsui, M.Inada, T.Ogawa, N.Ishida-Kitagawa, and T.Takeya (2011).
Identification and functional analysis of a new phosphorylation site (Y398) in the SH3 domain of Abi-1.
  FEBS Lett, 585, 834-840.  
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.  
20971646 S.S.Taylor, and A.P.Kornev (2011).
Protein kinases: evolution of dynamic regulatory proteins.
  Trends Biochem Sci, 36, 65-77.  
20870410 T.D.Bunney, and M.Katan (2011).
PLC regulation: emerging pictures for molecular mechanisms.
  Trends Biochem Sci, 36, 88-96.  
20585391 A.Dusa, C.Mouton, C.Pecquet, M.Herman, and S.N.Constantinescu (2010).
JAK2 V617F constitutive activation requires JH2 residue F595: a pseudokinase domain target for specific inhibitors.
  PLoS One, 5, e11157.  
  20139700 A.L.Munn, and P.Aspenström (2010).
Second international conference on F-BAR proteins: October 1-3, 2009 at Rånäs Slott, Sweden.
  Cell Adh Migr, 4, 81-93.  
20519627 D.W.Sherbenou, O.Hantschel, I.Kaupe, S.Willis, T.Bumm, L.P.Turaga, T.Lange, K.H.Dao, R.D.Press, B.J.Druker, G.Superti-Furga, and M.W.Deininger (2010).
BCR-ABL SH3-SH2 domain mutations in chronic myeloid leukemia patients on imatinib.
  Blood, 116, 3278-3285.  
20841568 J.Colicelli (2010).
ABL tyrosine kinases: evolution of function, regulation, and specificity.
  Sci Signal, 3, re6.  
19854302 J.Eswaran, and S.Knapp (2010).
Insights into protein kinase regulation and inhibition by large scale structural comparison.
  Biochim Biophys Acta, 1804, 429-432.  
20357770 J.Wojcik, O.Hantschel, F.Grebien, I.Kaupe, K.L.Bennett, J.Barkinge, R.B.Jones, A.Koide, G.Superti-Furga, and S.Koide (2010).
A potent and highly specific FN3 monobody inhibitor of the Abl SH2 domain.
  Nat Struct Mol Biol, 17, 519-527.
PDB code: 3k2m
20417104 M.Michael, A.Vehlow, C.Navarro, and M.Krause (2010).
c-Abl, Lamellipodin, and Ena/VASP proteins cooperate in dorsal ruffling of fibroblasts and axonal morphogenesis.
  Curr Biol, 20, 783-791.  
20336234 O.A.Gani, and R.A.Engh (2010).
Protein kinase inhibition of clinically important staurosporine analogues.
  Nat Prod Rep, 27, 489-498.  
20541610 P.Savitsky, J.Bray, C.D.Cooper, B.D.Marsden, P.Mahajan, N.A.Burgess-Brown, and O.Gileadi (2010).
High-throughput production of human proteins for crystallization: the SGC experience.
  J Struct Biol, 172, 3.  
20979614 V.Prieto-Echagüe, A.Gucwa, D.A.Brown, and W.T.Miller (2010).
Regulation of Ack1 localization and activity by the amino-terminal SAM domain.
  BMC Biochem, 11, 42.  
20495563 Y.L.Deribe, T.Pawson, and I.Dikic (2010).
Post-translational modifications in signal integration.
  Nat Struct Mol Biol, 17, 666-672.  
19489729 A.Edwards (2009).
Large-scale structural biology of the human proteome.
  Annu Rev Biochem, 78, 541-568.  
19610074 E.E.Thompson, A.P.Kornev, N.Kannan, C.Kim, L.F.Ten Eyck, and S.S.Taylor (2009).
Comparative surface geometry of the protein kinase family.
  Protein Sci, 18, 2016-2026.
PDB code: 3fjq
19513107 E.Zeqiraj, B.M.Filippi, S.Goldie, I.Navratilova, J.Boudeau, M.Deak, D.R.Alessi, and D.M.van Aalten (2009).
ATP and MO25alpha regulate the conformational state of the STRADalpha pseudokinase and activation of the LKB1 tumour suppressor.
  PLoS Biol, 7, e1000126.
PDB code: 3gni
19965465 J.D.Scott, and T.Pawson (2009).
Cell Signaling in Space and Time: Where Proteins Come Together and When They're Apart.
  Science, 326, 1220-1224.  
19665973 J.H.Bae, E.D.Lew, S.Yuzawa, F.Tomé, I.Lax, and J.Schlessinger (2009).
The selectivity of receptor tyrosine kinase signaling is controlled by a secondary SH2 domain binding site.
  Cell, 138, 514-524.
PDB codes: 3gqi 3gql
19721463 J.Weigelt (2009).
The case for open-access chemical biology. A strategy for pre-competitive medicinal chemistry to promote drug discovery.
  EMBO Rep, 10, 941-945.  
19244618 K.Huang, Y.H.Wang, A.Brown, and G.Sun (2009).
Identification of N-terminal lobe motifs that determine the kinase activity of the catalytic domains and regulatory strategies of Src and Csk protein tyrosine kinases.
  J Mol Biol, 386, 1066-1077.  
19703402 N.Halabi, O.Rivoire, S.Leibler, and R.Ranganathan (2009).
Protein sectors: evolutionary units of three-dimensional structure.
  Cell, 138, 774-786.  
19926274 P.Filippakopoulos, S.Müller, and S.Knapp (2009).
SH2 domains: modulators of nonreceptor tyrosine kinase activity.
  Curr Opin Struct Biol, 19, 643-649.  
19164531 R.E.Iacob, T.Pene-Dumitrescu, J.Zhang, N.S.Gray, T.E.Smithgall, and J.R.Engen (2009).
Conformational disturbance in Abl kinase upon mutation and deregulation.
  Proc Natl Acad Sci U S A, 106, 1386-1391.  
19290922 R.E.Joseph, and A.H.Andreotti (2009).
Conformational snapshots of Tec kinases during signaling.
  Immunol Rev, 228, 74-92.  
19679083 S.Müller, and S.Knapp (2009).
Out of the box binding determines specificity of SH2 domain interaction.
  Structure, 17, 1040-1041.  
19744855 T.J.Gibson (2009).
Cell regulation: determined to signal discrete cooperation.
  Trends Biochem Sci, 34, 471-482.  
19001085 V.A.McPherson, S.Everingham, R.Karisch, J.A.Smith, C.M.Udell, J.Zheng, Z.Jia, and A.W.Craig (2009).
Contributions of F-BAR and SH2 domains of Fes protein tyrosine kinase for coupling to the FcepsilonRI pathway in mast cells.
  Mol Cell Biol, 29, 389-401.  
19718043 V.Hindie, A.Stroba, H.Zhang, L.A.Lopez-Garcia, L.Idrissova, S.Zeuzem, D.Hirschberg, F.Schaeffer, T.J.Jørgensen, M.Engel, P.M.Alzari, and R.M.Biondi (2009).
Structure and allosteric effects of low-molecular-weight activators on the protein kinase PDK1.
  Nat Chem Biol, 5, 758-764.
PDB codes: 3hrc 3hrf
18796434 X.Cao, K.Q.Tanis, A.J.Koleske, and J.Colicelli (2008).
Enhancement of ABL kinase catalytic efficiency by a direct binding regulator is independent of other regulatory mechanisms.
  J Biol Chem, 283, 31401-31407.  
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.