PDBsum entry 2eu0

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Transferase PDB id
Protein chain
109 a.a. *
* Residue conservation analysis
PDB id:
Name: Transferase
Title: The nmr ensemble structure of the itk sh2 domain bound to a phosphopeptide
Structure: Tyrosine-protein kinase itk/tsk. Chain: a. Fragment: sh2 domain. Synonym: t-cell-specific kinase, il-2-inducible t-cell kinase, kinase emt, kinase tlk, itk. Engineered: yes. Lymphocyte cytosolic protein 2 phosphopeptide fragment. Chain: b.
Source: Mus musculus. House mouse. Organism_taxid: 10090. Gene: itk, emt, tlk, tsk. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008. Synthetic: yes. Other_details: this sequence occurs naturally in mus musculus (mouse)
NMR struc: 20 models
Authors: M.Sundd,E.V.Pletneva,D.B.Fulton,A.H.Andreotti
Key ref:
E.V.Pletneva et al. (2006). Molecular details of Itk activation by prolyl isomerization and phospholigand binding: the NMR structure of the Itk SH2 domain bound to a phosphopeptide. J Mol Biol, 357, 550-561. PubMed id: 16436281 DOI: 10.1016/j.jmb.2005.12.073
27-Oct-05     Release date:   07-Feb-06    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
Q03526  (ITK_MOUSE) -  Tyrosine-protein kinase ITK/TSK
625 a.a.
108 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 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
Bound ligand (Het Group name = PTR)
matches with 76.00% similarity
Molecule diagrams generated from .mol files obtained from the KEGG ftp site


DOI no: 10.1016/j.jmb.2005.12.073 J Mol Biol 357:550-561 (2006)
PubMed id: 16436281  
Molecular details of Itk activation by prolyl isomerization and phospholigand binding: the NMR structure of the Itk SH2 domain bound to a phosphopeptide.
E.V.Pletneva, M.Sundd, D.B.Fulton, A.H.Andreotti.
The Src homology 2 (SH2) domain of interleukin-2 tyrosine kinase (Itk) is a critical component of the regulatory apparatus controlling the activity of this immunologically important enzyme. To gain insight into the structural features associated with the activated form of Itk, we have solved the NMR structure of the SH2 domain bound to a phosphotyrosine-containing peptide (pY) and analyzed changes in trans-hydrogen bond scalar couplings ((3h)J(NC')) that result from pY binding. Isomerization of a single prolyl imide bond in this domain is responsible for simultaneous existence of two distinct SH2 conformers. Prolyl isomerization directs ligand recognition: the trans conformer preferentially binds pY. The structure of the SH2/pY complex provides insight into the ligand specificity; the BG loop in the ligand-free trans SH2 conformer is pre-arranged for optimal contacts with the pY+3 residue of the ligand. Analysis of (3h)J(NC') couplings arising from hydrogen bonds has revealed propagation of structural changes from the pY binding pocket to the CD loop containing conformationally heterogeneous proline as well as to the alphaB helix, on the opposite site of the domain. These findings offer a structural framework for understanding the roles of prolyl isomerization and pY binding in Itk regulation.
  Selected figure(s)  
Figure 2.
Figure 2. NMR structure of the Itk SH2 domain bound to the Ac-ADpYEPP-NH[2] phosphopeptide. (a) The 20 lowest energy structures of the Itk SH2/ADpYEPP complex. The peptide ligand is shown in red and the SH2 domain in turquoise. Backbone heavy atoms within the secondary structural elements over the entire SH2 sequence were used for superpositions. (b) Ribbon diagram of the energy minimized average structure of the Itk SH2/phosphopeptide complex. (The view is identical with that shown in (a).) Regular secondary structural elements and loop regions are labeled. The location of Pro287 within the CD loop is indicated. The phosphopeptide ligand (Ac-ADpYEPP-NH[2]) is red and the phosphotyrosine (pY) and proline residue three positions C-terminal (pY+3) are labeled. In both (a) and (b) the first two residues of the phosphopeptide (AD) are not included for clarity. No NOEs are observed between this region of the peptide and the Itk SH2 domain.
Figure 3.
Figure 3. (a) Superposition of the minimized average structures of the cis SH2 domain (orange), the trans SH2 domain (light blue) and the phospholigand-bound SH2 domain (dark blue). The phospholigand is shown in red and the pY and pY+3 residues are labeled. The BG loop is indicated and the arrow shows the shift in position of the alpha carbon atom of Leu329 that accompanies isomerization of Pro287 from the cis to trans conformations. The structure of the BG loop for the phospholigand-bound SH2 domain (dark blue) is similar to that of BG loop in the ligand-free trans domain (light blue). (b) Superposition of the lowest energy structures of the Itk cis SH2 domain (20 structures), the trans SH2 domain (20 structures) and the SH2/phosphopeptide complex (20 structures). Colors correspond to those in (a). The ensemble of structures indicates that the BG loop in the cis SH2 structure (orange) adopts a range of conformations that differ from the conformational preferences of both the trans SH2 domain and the phospholigand bound SH2 domain. For both (a) and (b) backbone heavy atoms within the secondary structural elements were used for superpositions.
  The above figures are reprinted by permission from Elsevier: J Mol Biol (2006, 357, 550-561) copyright 2006.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21227701 T.Kaneko, S.S.Sidhu, and S.S.Li (2011).
Evolving specificity from variability for protein interaction domains.
  Trends Biochem Sci, 36, 183-190.  
19361414 A.Severin, R.E.Joseph, S.Boyken, D.B.Fulton, and A.H.Andreotti (2009).
Proline isomerization preorganizes the Itk SH2 domain for binding to the Itk SH3 domain.
  J Mol Biol, 387, 726-743.  
19132916 J.E.Smith-Garvin, G.A.Koretzky, and M.S.Jordan (2009).
T cell activation.
  Annu Rev Immunol, 27, 591-619.  
19425169 K.Huck, O.Feyen, T.Niehues, F.Rüschendorf, N.Hübner, H.J.Laws, T.Telieps, S.Knapp, H.H.Wacker, A.Meindl, H.Jumaa, and A.Borkhardt (2009).
Girls homozygous for an IL-2-inducible T cell kinase mutation that leads to protein deficiency develop fatal EBV-associated lymphoproliferation.
  J Clin Invest, 119, 1350-1358.  
19689375 N.Sahu, and A.August (2009).
ITK inhibitors in inflammation and immune-mediated disorders.
  Curr Top Med Chem, 9, 690-703.  
19290922 R.E.Joseph, and A.H.Andreotti (2009).
Conformational snapshots of Tec kinases during signaling.
  Immunol Rev, 228, 74-92.  
19523959 R.E.Joseph, A.Severin, L.Min, D.B.Fulton, and A.H.Andreotti (2009).
SH2-dependent autophosphorylation within the Tec family kinase Itk.
  J Mol Biol, 391, 164-177.  
19617535 U.Weininger, R.P.Jakob, B.Eckert, K.Schweimer, F.X.Schmid, and J.Balbach (2009).
A remote prolyl isomerization controls domain assembly via a hydrogen bonding network.
  Proc Natl Acad Sci U S A, 106, 12335-12340.  
18342008 M.S.Jordan, J.E.Smith, J.C.Burns, J.E.Austin, K.E.Nichols, A.C.Aschenbrenner, and G.A.Koretzky (2008).
Complementation in trans of altered thymocyte development in mice expressing mutant forms of the adaptor molecule SLP76.
  Immunity, 28, 359-369.  
18599349 N.Isakov (2008).
A new twist to adaptor proteins contributes to regulation of lymphocyte cell signaling.
  Trends Immunol, 29, 388-396.  
17918167 A.Zhang, and A.D.Schlüter (2007).
Multigram solution-phase synthesis of three diastereomeric tripeptidic second-generation dendrons based on (2S,4S)-, (2S,4R)-, and (2R,4S)-4-aminoprolines.
  Chem Asian J, 2, 1540-1548.  
17823247 D.Hamelberg, T.Shen, and J.A.McCammon (2007).
A proposed signaling motif for nuclear import in mRNA processing via the formation of arginine claw.
  Proc Natl Acad Sci U S A, 104, 14947-14951.  
17937625 D.Wildemann, B.Hernandez Alvarez, G.Stoller, X.Z.Zhou, K.P.Lu, F.Erdmann, D.Ferrari, and G.Fischer (2007).
An essential role for Pin1 in Xenopus laevis embryonic development revealed by specific inhibitors.
  Biol Chem, 388, 1103-1111.  
17876319 K.P.Lu, G.Finn, T.H.Lee, and L.K.Nicholson (2007).
Prolyl cis-trans isomerization as a molecular timer.
  Nat Chem Biol, 3, 619-629.  
17289588 P.Sarkar, C.Reichman, T.Saleh, R.B.Birge, and C.G.Kalodimos (2007).
Proline cis-trans isomerization controls autoinhibition of a signaling protein.
  Mol Cell, 25, 413-426.  
16969585 K.C.Huang, H.T.Cheng, M.T.Pai, S.R.Tzeng, and J.W.Cheng (2006).
Solution structure and phosphopeptide binding of the SH2 domain from the human Bruton's tyrosine kinase.
  J Biomol NMR, 36, 73-78.
PDB code: 2ge9
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.