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PDBsum entry 1csz

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protein ligands links
Complex (phosphotransferase/peptide) PDB id
1csz
Jmol
Contents
Protein chain
112 a.a. *
Ligands
ACE-THR-PTR-GLU-
THR-LEU-NH2
* Residue conservation analysis
PDB id:
1csz
Name: Complex (phosphotransferase/peptide)
Title: Syk tyrosine kinasE C-terminal sh2 domain complexed with a phosphopeptidefrom the gamma chain of the high affinity imm g receptor, nmr
Structure: Syk protein tyrosine kinase. Chain: a. Fragment: c-terminal sh2 domain. Engineered: yes. Acetyl-thr-ptr-glu-thr-leu-nh2. Chain: b. Engineered: yes. Other_details: the ligand is a phosphotyrosine containing p derived from the high-affinity ige receptor
Source: Homo sapiens. Human. Organism_taxid: 9606. Cell_line: bl21. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008. Other_details: recombinant construct added to protein domai
NMR struc: 1 models
Authors: S.S.Narula,R.W.Yuan,S.E.Adams,O.M.Green,J.Green,T.B.Phillips L.D.Zydowsky,M.C.Botfield,M.H.Hatada,E.R.Laird,M.J.Zoller,J D.C.Dalgarno
Key ref:
S.S.Narula et al. (1995). Solution structure of the C-terminal SH2 domain of the human tyrosine kinase Syk complexed with a phosphotyrosine pentapeptide. Structure, 3, 1061-1073. PubMed id: 8590001 DOI: 10.1016/S0969-2126(01)00242-8
Date:
03-Oct-95     Release date:   08-Nov-96    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P43405  (KSYK_HUMAN) -  Tyrosine-protein kinase SYK
Seq:
Struc:
 
Seq:
Struc:
635 a.a.
112 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 9 residue positions (black crosses)

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

 

 
    reference    
 
 
DOI no: 10.1016/S0969-2126(01)00242-8 Structure 3:1061-1073 (1995)
PubMed id: 8590001  
 
 
Solution structure of the C-terminal SH2 domain of the human tyrosine kinase Syk complexed with a phosphotyrosine pentapeptide.
S.S.Narula, R.W.Yuan, S.E.Adams, O.M.Green, J.Green, T.B.Philips, L.D.Zydowsky, M.C.Botfield, M.Hatada, E.R.Laird.
 
  ABSTRACT  
 
BACKGROUND: Recruitment of the intracellular tyrosine kinase Syk to activated immune-response receptors is a critical early step in intracellular signaling. In mast cells, Syk specifically associates with doubly phosphorylated immunoreceptor tyrosine-based activation motifs (ITAMs) that are found within the IgE receptor. The mechanism by which Syk recognizes these motifs is not fully understood. Both Syk SH2 (Src homology 2) domains are required for high-affinity binding to these motifs, but the C-terminal SH2 domain (Syk-C) can function independently and can bind, in isolation, to the tyrosine-phosphorylated IgE receptor in vitro. In order to improve understanding of the cellular function of Syk, we have determined the solution structure of Syk-C complexed with a phosphotyrosine peptide derived from the gamma subunit of the IgE receptor. RESULTS: The Syk-C:peptide structure is compared with liganded structures of both the SH2 domain of Src and the C-terminal SH2 domain of ZAP-70 (the 70 kDa zeta-associated protein). The topologies of these domains are similar, although significant differences occur in the loop regions. In the Syk-C structure, the phosphotyrosine and leucine residues of the peptide ligand interact with pockets on the protein, and the intervening residues are extended. CONCLUSIONS: Syk-C resembles other SH2 domains in its peptide-binding interactions and overall topology, a result that is consistent with its ability to function as an independent SH2 domain in vitro. This result suggests that Syk-C plays a unique role in the intact Syk protein. The determinants of the binding affinity and selectivity of Syk-C may reside in the least-conserved structural elements that comprise the phosphotyrosine- and leucine-binding sites. These structural features can be exploited for the design of Syk-selective SH2 antagonists for the treatment of allergic disorders and asthma.
 
  Selected figure(s)  
 
Figure 1.
Figure 1. Sequences for selected SH2 domains —v-Src (avian Src SH2), c-Src (human Src SH2), Syk-C (human Syk C-terminal SH2), ZAP-C (human ZAP-70 C-terminal SH2) PLCγ1-C (bovine phospholipase C-γ1 C-terminal SH2—aligned according to the secondary structure definitions of Src SH2 and using the nomenclature of Eck et al. [23]. The first residue in the alignment corresponds to Trp15 of the Syk-C construct reported here and Trp168 for the full sequence of human Syk. Secondary structural regions specific to Syk-C SH2 are highlighted in gray. Residues in v-Src that are implicated in binding to phosphotyrosine-containing peptides are highlighted in green (residues that contact pTyr), red (pTyr+1), yellow (pTyr+2), and purple (pTyr+3) [29]. Figure 1. Sequences for selected SH2 domains —v-Src (avian Src SH2), c-Src (human Src SH2), Syk-C (human Syk C-terminal SH2), ZAP-C (human ZAP-70 C-terminal SH2) PLCγ1-C (bovine phospholipase C-γ1 C-terminal SH2—aligned according to the secondary structure definitions of Src SH2 and using the nomenclature of Eck et al. [[3]23]. The first residue in the alignment corresponds to Trp15 of the Syk-C construct reported here and Trp168 for the full sequence of human Syk. Secondary structural regions specific to Syk-C SH2 are highlighted in gray. Residues in v-Src that are implicated in binding to phosphotyrosine-containing peptides are highlighted in green (residues that contact pTyr), red (pTyr+1), yellow (pTyr+2), and purple (pTyr+3) [[4]29].
Figure 7.
Figure 7. Schematic illustrations of the interactions of the pTyr76 peptide residues with Syk-C. (a) pTyr:Syk-C interactions. (b) Interactions of the pTyr+1 (Glu3), pTyr+2 (Thr4), and pTyr+3 (Leu5) residues with Syk-C. The peptide residues are marked in oval, whereas the protein residues are labeled according to their name and position in the secondary structure, and are marked in rectangles (Figure 1). Dashed lines represent observed peptide:protein NOEs, whereas dotted lines represent inferred interactions (see text). In order to simplify the figure, when multiple NOE interactions from an amino-acid side chain are present, curved lines have been used to group side-chain protons that have similar NOEs. Figure 7. Schematic illustrations of the interactions of the pTyr76 peptide residues with Syk-C. (a) pTyr:Syk-C interactions. (b) Interactions of the pTyr+1 (Glu3), pTyr+2 (Thr4), and pTyr+3 (Leu5) residues with Syk-C. The peptide residues are marked in oval, whereas the protein residues are labeled according to their name and position in the secondary structure, and are marked in rectangles ([4]Figure 1). Dashed lines represent observed peptide:protein NOEs, whereas dotted lines represent inferred interactions (see text). In order to simplify the figure, when multiple NOE interactions from an amino-acid side chain are present, curved lines have been used to group side-chain protons that have similar NOEs.
 
  The above figures are reprinted by permission from Cell Press: Structure (1995, 3, 1061-1073) copyright 1995.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
19763316 J.Kuil, H.M.Branderhorst, R.J.Pieters, N.J.de Mol, and R.M.Liskamp (2009).
ITAM-derived phosphopeptide-containing dendrimers as multivalent ligands for Syk tandem SH2 domain.
  Org Biomol Chem, 7, 4088-4094.  
19306898 R.L.Geahlen (2009).
Syk and pTyr'd: Signaling through the B cell antigen receptor.
  Biochim Biophys Acta, 1793, 1115-1127.  
18484636 T.Ozawa, and K.Okazaki (2008).
CH/pi hydrogen bonds determine the selectivity of the Src homology 2 domain to tyrosine phosphotyrosyl peptides: an ab initio fragment molecular orbital study.
  J Comput Chem, 29, 2656-2666.  
15914019 M.I.Catalina, M.J.Fischer, F.J.Dekker, R.M.Liskamp, and A.J.Heck (2005).
Binding of a diphosphorylated-ITAM peptide to spleen tyrosine kinase (Syk) induces distal conformational changes: a hydrogen exchange mass spectrometry study.
  J Am Soc Mass Spectrom, 16, 1039-1051.  
16252296 N.J.de Mol, M.I.Catalina, F.J.Dekker, M.J.Fischer, A.J.Heck, and R.M.Liskamp (2005).
Protein flexibility and ligand rigidity: a thermodynamic and kinetic study of ITAM-based ligand binding to Syk tandem SH2.
  Chembiochem, 6, 2261-2270.  
11828442 R.Ruijtenbeek, J.A.Kruijtzer, W.van de Wiel, M.J.Fischer, M.Flück, F.A.Redegeld, R.M.Liskamp, and F.P.Nijkamp (2001).
Peptoid - peptide hybrids that bind Syk SH2 domains involved in signal transduction.
  Chembiochem, 2, 171-179.  
10438475 P.G.Swann, S.Odom, Y.J.Zhou, Z.Szallasi, P.M.Blumberg, P.Draber, and J.Rivera (1999).
Requirement for a negative charge at threonine 60 of the FcRgamma for complete activation of Syk.
  J Biol Chem, 274, 23068-23077.  
9422724 E.A.Ottinger, M.C.Botfield, and S.E.Shoelson (1998).
Tandem SH2 domains confer high specificity in tyrosine kinase signaling.
  J Biol Chem, 273, 729-735.  
9817027 T.K.Sawyer (1998).
Src homology-2 domains: structure, mechanisms, and drug discovery.
  Biopolymers, 47, 243-261.  
  9300491 A.U.Singer, and J.D.Forman-Kay (1997).
pH titration studies of an SH2 domain-phosphopeptide complex: unusual histidine and phosphate pKa values.
  Protein Sci, 6, 1910-1919.  
9153411 B.Gay, P.Furet, C.García-Echeverría, J.Rahuel, P.Chène, H.Fretz, J.Schoepfer, and G.Caravatti (1997).
Dual specificity of Src homology 2 domains for phosphotyrosine peptide ligands.
  Biochemistry, 36, 5712-5718.  
9241420 J.Kuriyan, and D.Cowburn (1997).
Modular peptide recognition domains in eukaryotic signaling.
  Annu Rev Biophys Biomol Struct, 26, 259-288.  
9143687 M.Daëron (1997).
Fc receptor biology.
  Annu Rev Immunol, 15, 203-234.  
  9651784 M.Daëron (1997).
Structural bases of Fc gamma R functions.
  Int Rev Immunol, 16, 1.  
9351806 T.D.Mulhern, G.L.Shaw, C.J.Morton, A.J.Day, and I.D.Campbell (1997).
The SH2 domain from the tyrosine kinase Fyn in complex with a phosphotyrosyl peptide reveals insights into domain stability and binding specificity.
  Structure, 5, 1313-1323.
PDB codes: 1aot 1aou
  8670861 A.L.Breeze, B.V.Kara, D.G.Barratt, M.Anderson, J.C.Smith, R.W.Luke, J.R.Best, and S.A.Cartlidge (1996).
Structure of a specific peptide complex of the carboxy-terminal SH2 domain from the p85 alpha subunit of phosphatidylinositol 3-kinase.
  EMBO J, 15, 3579-3589.
PDB code: 1pic
8673601 J.Rahuel, B.Gay, D.Erdmann, A.Strauss, C.Garcia-Echeverría, P.Furet, G.Caravatti, H.Fretz, J.Schoepfer, and M.G.Grütter (1996).
Structural basis for specificity of Grb2-SH2 revealed by a novel ligand binding mode.
  Nat Struct Biol, 3, 586-589.
PDB code: 1tze
8794768 K.H.Thornton, W.T.Mueller, P.McConnell, G.Zhu, A.R.Saltiel, and V.Thanabal (1996).
Nuclear magnetic resonance solution structure of the growth factor receptor-bound protein 2 Src homology 2 domain.
  Biochemistry, 35, 11852-11864.
PDB code: 1ghu
8639560 W.J.Metzler, B.Leiting, K.Pryor, L.Mueller, and B.T.Farmer (1996).
The three-dimensional solution structure of the SH2 domain from p55blk kinase.
  Biochemistry, 35, 6201-6211.
PDB codes: 1blj 1blk
8590006 B.J.Mayer (1995).
Why two heads are better.
  Structure, 3, 977-980.  
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.