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PDBsum entry 1hcs

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Complex (signal transduction/peptide) PDB id
1hcs
Jmol
Contents
Protein chain
107 a.a. *
Ligands
ACE-PTR-GLU-GLU-
ILE-GLU
* Residue conservation analysis
PDB id:
1hcs
Name: Complex (signal transduction/peptide)
Title: Nmr structure of the human src sh2 domain complex
Structure: Acetyl-pyeeie-oh. Chain: a. Engineered: yes. Human src. Chain: b. Synonym: pp60==c-src==. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: nucleotide sequence a. Expressed in: escherichia coli bl21. Expression_system_taxid: 511693.
NMR struc: 1 models
Authors: R.T.Gampe Junior,R.X.Xu
Key ref:
R.X.Xu et al. (1995). Solution structure of the human pp60c-src SH2 domain complexed with a phosphorylated tyrosine pentapeptide. Biochemistry, 34, 2107-2121. PubMed id: 7532003
Date:
02-Sep-94     Release date:   15-Sep-95    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P12931  (SRC_HUMAN) -  Proto-oncogene tyrosine-protein kinase Src
Seq:
Struc:
 
Seq:
Struc:
536 a.a.
107 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
Bound ligand (Het Group name = PTR)
matches with 76.00% similarity
Molecule diagrams generated from .mol files obtained from the KEGG ftp site

 

 
    reference    
 
 
Biochemistry 34:2107-2121 (1995)
PubMed id: 7532003  
 
 
Solution structure of the human pp60c-src SH2 domain complexed with a phosphorylated tyrosine pentapeptide.
R.X.Xu, J.M.Word, D.G.Davis, M.J.Rink, D.H.Willard, R.T.Gampe.
 
  ABSTRACT  
 
Human pp60c-src is a cellular nonreceptor tyrosine kinase that participates in cytosolic signal transduction and has been implicated in the development of malignant tumors in the human breast and colon. Signal transduction is mediated by highly specific interactions between the SH2 domain and receptor phosphorylated tyrosine binding motifs. To elucidate the molecular conformation and interactions in solution, a family of highly resolved nuclear magnetic resonance (NMR) structures was determined for the src SH2 domain complexed with a high-affinity phosphorylated pentapeptide, acetyl-p YEEIE-OH. The 23 structures, generated with a distance geometry (DG) and a dynamical simulated annealing (SA) procedure, satisfied 2072 experimental restraints derived from a variety of multifrequency/multidimensional and isotope-filtered NMR data. Superimposition of residues 143-245 upon the mean coordinate set yielded an atomic rmsd of 0.58 +/- 0.09 A for the N, C alpha, C' atoms and 1.04 +/- 0.08 for all the non-hydrogen atoms. Residues in the ordered secondary structure regions superimpose to 0.29 +/- 0.04 A for the N, C alpha, C' and 0.73 +/- 0.08 A for all the non-hydrogen atoms. The angular order parameter calculated for the phi, psi angles was > 0.9 for 81 of the 106 protein residues. The main protein conformational features are three antiparallel beta-strands that traverse a compact core with an alpha-helix on each side of the core near the N- and C-termini. The observed intermolecular nuclear Overhauser effects (NOE) from the pY, +1E, and +3I residues positioned the ligand in an extended conformation across the SH2 domain surface with the pY and +3I side chains inserted into the protein binding pockets. In general, the protein conformation is consistent with previously reported structures of different SH2 domain complexes determined by X-ray crystallography. However, inter- or intramolecular interactions involving the guanidinium side chains of the solvated R alpha A2 or the buried R beta B5 were not observed at pH = 5.5 or 7.0. If such interactions exist in solution, the absence of any confirming data probably arises from rapid exchange with solvent and/or undetermined dynamic components. Thus, the unrestrained R alpha A2 side chain did not show an amino-aromatic interaction or a hydrogen bond to the -1 carbonyl oxygen as observed in the crystal structures. This result is consistent with the solution structure of a different SH2 domain complex. A more detailed comparison between the crystal structure and the NMR-derived solution structures of the same src SH2 domain complex is presented.(ABSTRACT TRUNCATED AT 400 WORDS)
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
20154139 A.Csiszar, E.Vogelsang, H.Beug, and M.Leptin (2010).
A novel conserved phosphotyrosine motif in the Drosophila fibroblast growth factor signaling adaptor Dof with a redundant role in signal transmission.
  Mol Cell Biol, 30, 2017-2027.  
20574521 J.Nachman, G.Gish, C.Virag, T.Pawson, R.Pomès, and E.Pai (2010).
Conformational determinants of phosphotyrosine peptides complexed with the Src SH2 domain.
  PLoS One, 5, e11215.  
19334714 P.K.Mandal, D.Limbrick, D.R.Coleman, G.A.Dyer, Z.Ren, J.S.Birtwistle, C.Xiong, X.Chen, J.M.Briggs, and J.S.McMurray (2009).
Conformationally constrained peptidomimetic inhibitors of signal transducer and activator of transcription. 3: Evaluation and molecular modeling.
  J Med Chem, 52, 2429-2442.  
18494800 A.W.Perriman, M.A.Apponyi, M.A.Buntine, R.J.Jackway, M.W.Rutland, J.W.White, and J.H.Bowie (2008).
Surface movement in water of splendipherin, the aquatic male sex pheromone of the tree frog Litoria splendida.
  FEBS J, 275, 3362-3374.  
18536014 J.D.Taylor, A.Ababou, R.R.Fawaz, C.J.Hobbs, M.A.Williams, and J.E.Ladbury (2008).
Structure, dynamics, and binding thermodynamics of the v-Src SH2 domain: implications for drug design.
  Proteins, 73, 929-940.
PDB code: 2jyq
18058821 J.S.McMurray (2008).
Structural basis for the binding of high affinity phosphopeptides to Stat3.
  Biopolymers, 90, 69-79.  
18361454 M.A.Dolan, M.Keil, and D.S.Baker (2008).
Comparison of composer and ORCHESTRAR.
  Proteins, 72, 1243-1258.  
15894543 S.Radtke, S.Haan, A.Jörissen, H.M.Hermanns, S.Diefenbach, T.Smyczek, H.Schmitz-Vandeleur, P.C.Heinrich, I.Behrmann, and C.Haan (2005).
The Jak1 SH2 domain does not fulfill a classical SH2 function in Jak/STAT signaling but plays a structural role for receptor interaction and up-regulation of receptor surface expression.
  J Biol Chem, 280, 25760-25768.  
14579314 C.S.Brinkworth, J.A.Carver, K.L.Wegener, J.Doyle, L.E.Llewellyn, and J.H.Bowie (2003).
The solution structure of frenatin 3, a neuronal nitric oxide synthase inhibitor from the giant tree frog, Litoria infrafrenata.
  Biopolymers, 70, 424-434.  
12493827 D.D.Ojennus, S.E.Lehto, and D.S.Wuttke (2003).
Electrostatic interactions in the reconstitution of an SH2 domain from constituent peptide fragments.
  Protein Sci, 12, 44-55.  
12707266 D.Man, W.He, K.H.Sze, K.Gong, D.K.Smith, G.Zhu, and N.Y.Ip (2003).
Solution structure of the C-terminal domain of the ciliary neurotrophic factor (CNTF) receptor and ligand free associations among components of the CNTF receptor complex.
  J Biol Chem, 278, 23285-23294.
PDB code: 1uc6
12631273 J.Doyle, C.S.Brinkworth, K.L.Wegener, J.A.Carver, L.E.Llewellyn, I.N.Olver, J.H.Bowie, P.A.Wabnitz, and M.J.Tyler (2003).
nNOS inhibition, antimicrobial and anticancer activity of the amphibian skin peptide, citropin 1.1 and synthetic modifications. The solution structure of a modified citropin 1.1.
  Eur J Biochem, 270, 1141-1153.  
12717721 K.L.Wegener, J.A.Carver, and J.H.Bowie (2003).
The solution structures and activity of caerin 1.1 and caerin 1.4 in aqueous trifluoroethanol and dodecylphosphocholine micelles.
  Biopolymers, 69, 42-59.  
12384576 L.W.Donaldson, G.Gish, T.Pawson, L.E.Kay, and J.D.Forman-Kay (2002).
Structure of a regulatory complex involving the Abl SH3 domain, the Crk SH2 domain, and a Crk-derived phosphopeptide.
  Proc Natl Acad Sci U S A, 99, 14053-14058.
PDB code: 1ju5
12027890 M.Hörtner, U.Nielsch, L.M.Mayr, P.C.Heinrich, and S.Haan (2002).
A new high affinity binding site for suppressor of cytokine signaling-3 on the erythropoietin receptor.
  Eur J Biochem, 269, 2516-2526.  
11604523 D.D.Ojennus, M.R.Fleissner, and D.S.Wuttke (2001).
Reconstitution of a native-like SH2 domain from disordered peptide fragments examined by multidimensional heteronuclear NMR.
  Protein Sci, 10, 2162-2175.  
10727928 B.C.Chia, J.A.Carver, T.D.Mulhern, and J.H.Bowie (2000).
Maculatin 1.1, an anti-microbial peptide from the Australian tree frog, Litoria genimaculata solution structure and biological activity.
  Eur J Biochem, 267, 1894-1908.  
  11106171 D.A.Henriques, J.E.Ladbury, and R.M.Jackson (2000).
Comparison of binding energies of SrcSH2-phosphotyrosyl peptides with structure-based prediction using surface area based empirical parameterization.
  Protein Sci, 9, 1975-1985.  
10951191 T.Rozek, K.L.Wegener, J.H.Bowie, I.N.Olver, J.A.Carver, J.C.Wallace, and M.J.Tyler (2000).
The antibiotic and anticancer active aurein peptides from the Australian Bell Frogs Litoria aurea and Litoria raniformis the solution structure of aurein 1.2.
  Eur J Biochem, 267, 5330-5341.  
10461748 B.C.Chia, J.A.Carver, T.D.Mulhern, and J.H.Bowie (1999).
The solution structure of uperin 3.6, an antibiotic peptide from the granular dorsal glands of the Australian toadlet, Uperoleia mjobergii.
  J Pept Res, 54, 137-145.  
10504394 K.L.Wegener, P.A.Wabnitz, J.A.Carver, J.H.Bowie, B.C.Chia, J.C.Wallace, and M.J.Tyler (1999).
Host defence peptides from the skin glands of the Australian blue mountains tree-frog Litoria citropa. Solution structure of the antibacterial peptide citropin 1.1.
  Eur J Biochem, 265, 627-637.  
9417118 J.W.Thomas, B.Ellis, R.J.Boerner, W.B.Knight, G.C.White, and M.D.Schaller (1998).
SH2- and SH3-mediated interactions between focal adhesion kinase and Src.
  J Biol Chem, 273, 577-583.  
9871733 K.J.Alligood, P.S.Charifson, R.Crosby, T.G.Consler, P.L.Feldman, R.T.Gampe, T.M.Gilmer, S.R.Jordan, M.W.Milstead, C.Mohr, M.R.Peel, W.Rocque, M.Rodriguez, D.W.Rusnak, L.M.Shewchuk, and D.D.Sternbach (1998).
The formation of a covalent complex between a dipeptide ligand and the src SH2 domain.
  Bioorg Med Chem Lett, 8, 1189-1194.  
  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.  
9254595 C.McNemar, M.E.Snow, W.T.Windsor, A.Prongay, P.Mui, R.Zhang, J.Durkin, H.V.Le, and P.C.Weber (1997).
Thermodynamic and structural analysis of phosphotyrosine polypeptide binding to Grb2-SH2.
  Biochemistry, 36, 10006-10014.  
9241420 J.Kuriyan, and D.Cowburn (1997).
Modular peptide recognition domains in eukaryotic signaling.
  Annu Rev Biophys Biomol Struct, 26, 259-288.  
9360978 L.Oligino, F.D.Lung, L.Sastry, J.Bigelow, T.Cao, M.Curran, T.R.Burke, S.Wang, D.Krag, P.P.Roller, and C.R.King (1997).
Nonphosphorylated peptide ligands for the Grb2 Src homology 2 domain.
  J Biol Chem, 272, 29046-29052.  
9043656 M.S.Plummer, E.A.Lunney, K.S.Para, A.Shahripour, C.J.Stankovic, C.Humblet, J.H.Fergus, J.S.Marks, R.Herrera, S.Hubbell, A.Saltiel, and T.K.Sawyer (1997).
Design of peptidomimetic ligands for the pp60src SH2 domain.
  Bioorg Med Chem, 5, 41-47.  
9174343 P.S.Charifson, L.M.Shewchuk, W.Rocque, C.W.Hummel, S.R.Jordan, C.Mohr, G.J.Pacofsky, M.R.Peel, M.Rodriguez, D.D.Sternbach, and T.G.Consler (1997).
Peptide ligands of pp60(c-src) SH2 domains: a thermodynamic and structural study.
  Biochemistry, 36, 6283-6293.
PDB codes: 1a07 1a08 1a09 1a1a 1a1b 1a1c 1a1e
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
8621421 C.W.Ward, K.H.Gough, M.Rashke, S.S.Wan, G.Tribbick, and J.Wang (1996).
Systematic mapping of potential binding sites for Shc and Grb2 SH2 domains on insulin receptor substrate-1 and the receptors for insulin, epidermal growth factor, platelet-derived growth factor, and fibroblast growth factor.
  J Biol Chem, 271, 5603-5609.  
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
8952511 U.L.Günther, Y.Liu, D.Sanford, W.W.Bachovchin, and B.Schaffhausen (1996).
NMR analysis of interactions of a phosphatidylinositol 3'-kinase SH2 domain with phosphotyrosine peptides reveals interdependence of major binding sites.
  Biochemistry, 35, 15570-15581.  
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
  8575189 A.M.Gronenborn, and G.M.Clore (1995).
Structures of protein complexes by multidimensional heteronuclear magnetic resonance spectroscopy.
  Crit Rev Biochem Mol Biol, 30, 351-385.  
8564419 K.Ramalingam, S.R.Eaton, W.L.Cody, G.H.Lu, R.L.Panek, L.A.Waite, S.J.Decker, J.A.Keiser, and A.M.Doherty (1995).
Structure-activity studies of phosphorylated peptide inhibitors of the association of phosphatidylinositol 3-kinase with PDGF-beta receptor.
  Bioorg Med Chem, 3, 1263-1272.  
8590001 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, and E.R.Laird (1995).
Solution structure of the C-terminal SH2 domain of the human tyrosine kinase Syk complexed with a phosphotyrosine pentapeptide.
  Structure, 3, 1061-1073.
PDB codes: 1csy 1csz
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.