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PDBsum entry 1a07
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protein ligands Protein-protein interface(s) links
Complex (transferase/peptide) PDB id
1a07

 

 

 

 

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Contents
Protein chains
105 a.a. *
Ligands
ACE-PTR-GLU-DIP ×2
Waters ×150
* Residue conservation analysis
PDB id:
1a07
Name: Complex (transferase/peptide)
Title: C-src (sh2 domain) complexed with ace-malonyl tyr-glu-(n,n-dipentyl amine)
Structure: C-src tyrosine kinase. Chain: a, b. Fragment: sh2 domain. Engineered: yes. Ace-malonyl tyr-glu-(n,n-dipentyl amine). Chain: c, d. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Cellular_location: cytoplasm. Gene: src. Expressed in: escherichia coli bl21. Expression_system_taxid: 511693.
Biol. unit: Monomer (from PDB file)
Resolution:
2.20Å     R-factor:   0.192    
Authors: L.Shewchuk,S.Jordan
Key ref:
P.S.Charifson et al. (1997). Peptide ligands of pp60(c-src) SH2 domains: a thermodynamic and structural study. Biochemistry, 36, 6283-6293. PubMed id: 9174343 DOI: 10.1021/bi970019n
Date:
09-Dec-97     Release date:   08-Apr-98    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P12931  (SRC_HUMAN) -  Proto-oncogene tyrosine-protein kinase Src from Homo sapiens
Seq:
Struc: 		 
Seq:
Struc: 		536 a.a.
105 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.2.7.10.2  - non-specific protein-tyrosine kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H+
L-tyrosyl-[protein]
 + ATP
 = O-phospho-L-tyrosyl-[protein]
 + ADP
 + H(+)
Molecule diagrams generated from .mol files obtained from the KEGG ftp site

 

 
    Added reference    
 
 
DOI no: 10.1021/bi970019n Biochemistry 36:6283-6293 (1997)
PubMed id: 9174343  
 
 
Peptide ligands of pp60(c-src) SH2 domains: a thermodynamic and structural study.
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, T.G.Consler.
 
  ABSTRACT  
 
Thermodynamic measurements, structural determinations, and molecular computations were applied to a series of peptide ligands of the pp60(c-src) SH2 domain in an attempt to understand the critical binding determinants for this class of molecules. Isothermal titration calorimetry (ITC) measurements were combined with structural data derived from X-ray crystallographic studies on 12 peptide-SH2 domain complexes. The peptide ligands studied fall into two general classes: (1) dipeptides of the general framework N-acetylphosphotyrosine (or phosphotyrosine replacement)-Glu or methionine (or S-methylcysteine)-X, where X represents a hydrophobic amine, and (2) tetra- or pentapeptides of the general framework N-acetylphosphotyrosine-Glu-Glu-Ile-X, where X represents either Glu, Gln, or NH2. Dipeptide analogs which featured X as either hexanolamine or heptanolamine were able to pick up new hydrogen bonds involving their hydroxyl groups within a predominantly lipophilic surface cavity. However, due to internal strain as well as the solvent accessibility of the new hydrogen bonds formed, no net increase in binding affinity was observed. Phosphatase-resistant benzylmalonate and alpha,alpha-difluorobenzyl phosphonate analogs of phosphotyrosine retained some binding affinity for the pp60(c-src) SH2 domain but caused local structural perturbations in the phosphotyrosine-binding site. In the case where a reversible covalent thiohemiacetal was formed between a formylated phosphotyrosine analog and the thiol side chain of Cys-188, deltaS was 25.6 cal/(mol K) lower than for the nonformylated phosphotyrosine parent. Normal mode calculations show that the dramatic decrease in entropy observed for the covalent thiohemiacetal complex is due to the inability of the phosphotyrosine moiety to transform lost rotational and translational degrees of freedom into new vibrational modes.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
20501602 M.L.Hekkelman, T.A.Te Beek, S.R.Pettifer, D.Thorne, T.K.Attwood, and G.Vriend (2010).
WIWS: a protein structure bioinformatics Web service collection.
  Nucleic Acids Res, 38, W719-W723.  
19241406 L.Röglin, F.Altenbrunn, and O.Seitz (2009).
DNA and RNA-controlled switching of protein kinase activity.
  Chembiochem, 10, 758-765.  
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
17164528 C.W.Chung (2007).
The use of biophysical methods increases success in obtaining liganded crystal structures.
  Acta Crystallogr D Biol Crystallogr, 63, 62-71.  
16257377 G.A.Holdgate, and W.H.Ward (2005).
Measurements of binding thermodynamics in drug discovery.
  Drug Discov Today, 10, 1543-1550.  
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.  
15377393 W.Cai, J.Pei, and N.V.Grishin (2004).
Reconstruction of ancestral protein sequences and its applications.
  BMC Evol Biol, 4, 33.  
12210999 I.Luque, and E.Freire (2002).
Structural parameterization of the binding enthalpy of small ligands.
  Proteins, 49, 181-190.  
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.  
11809769 S.C.Pero, L.Oligino, R.J.Daly, A.L.Soden, C.Liu, P.P.Roller, P.Li, and D.N.Krag (2002).
Identification of novel non-phosphorylated ligands, which bind selectively to the SH2 domain of Grb7.
  J Biol Chem, 277, 11918-11926.  
11746693 G.M.Verkhivker, D.Bouzida, D.K.Gehlhaar, P.A.Rejto, L.Schaffer, S.Arthurs, A.B.Colson, S.T.Freer, V.Larson, B.A.Luty, T.Marrone, and P.W.Rose (2001).
Hierarchy of simulation models in predicting molecular recognition mechanisms from the binding energy landscapes: structural analysis of the peptide complexes with SH2 domains.
  Proteins, 45, 456-470.  
11425533 R.Sundaramoorthi, C.Siedem, C.B.Vu, D.C.Dalgarno, E.C.Laird, M.C.Botfield, A.B.Combs, S.E.Adams, R.W.Yuan, M.Weigele, and S.S.Narula (2001).
Selective inhibition of Src SH2 by a novel thiol-targeting tricarbonyl-modified inhibitor and mechanistic analysis by (1)H/(13)C NMR spectroscopy.
  Bioorg Med Chem Lett, 11, 1665-1669.  
11470604 W.C.Shakespeare (2001).
SH2 domain inhibition: a problem solved?
  Curr Opin Chem Biol, 5, 409-415.  
11459664 Y.T.Chen, M.B.Onaran, C.J.Doss, and C.T.Seto (2001).
alpha-Ketocarboxylic acid-based inhibitors of protein tyrosine phosphatases.
  Bioorg Med Chem Lett, 11, 1935-1938.  
  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.  
10712930 S.M.Violette, W.C.Shakespeare, C.Bartlett, W.Guan, J.A.Smith, R.J.Rickles, R.S.Bohacek, D.A.Holt, R.Baron, and T.K.Sawyer (2000).
A Src SH2 selective binding compound inhibits osteoclast-mediated resorption.
  Chem Biol, 7, 225-235.  
  10850802 S.P.Edgcomb, B.M.Baker, and K.P.Murphy (2000).
The energetics of phosphate binding to a protein complex.
  Protein Sci, 9, 927-933.  
10978163 W.Chen, M.Wilborn, and J.Rudolph (2000).
Dual-specific Cdc25B phosphatase: in search of the catalytic acid.
  Biochemistry, 39, 10781-10789.  
10944210 W.Shakespeare, M.Yang, R.Bohacek, F.Cerasoli, K.Stebbins, R.Sundaramoorthi, M.Azimioara, C.Vu, S.Pradeepan, C.Metcalf, C.Haraldson, T.Merry, D.Dalgarno, S.Narula, M.Hatada, X.Lu, M.R.van Schravendijk, S.Adams, S.Violette, J.Smith, W.Guan, C.Bartlett, J.Herson, J.Iuliucci, M.Weigele, and T.Sawyer (2000).
Structure-based design of an osteoclast-selective, nonpeptide src homology 2 inhibitor with in vivo antiresorptive activity.
  Proc Natl Acad Sci U S A, 97, 9373-9378.
PDB code: 1fbz
10476868 J.L.Buchanan, R.S.Bohacek, G.P.Luke, M.Hatada, X.Lu, D.C.Dalgarno, S.S.Narula, R.Yuan, and D.A.Holt (1999).
Structure-based design and synthesis of a novel class of Src SH2 inhibitors.
  Bioorg Med Chem Lett, 9, 2353-2358.  
10413509 M.R.Holbrook, J.B.O'Donnell, L.L.Slakey, and D.J.Gross (1999).
Epidermal growth factor receptor internalization rate is regulated by negative charges near the SH2 binding site Tyr992.
  Biochemistry, 38, 9348-9356.  
10398925 R.A.Grucza, J.M.Bradshaw, K.Fütterer, and G.Waksman (1999).
SH2 domains: from structure to energetics, a dual approach to the study of structure-function relationships.
  Med Res Rev, 19, 273-293.  
10213605 R.A.Grucza, K.Fütterer, A.C.Chan, and G.Waksman (1999).
Thermodynamic study of the binding of the tandem-SH2 domain of the Syk kinase to a dually phosphorylated ITAM peptide: evidence for two conformers.
  Biochemistry, 38, 5024-5033.  
9753693 E.Chung, D.Henriques, D.Renzoni, M.Zvelebil, J.M.Bradshaw, G.Waksman, C.V.Robinson, and J.E.Ladbury (1998).
Mass spectrometric and thermodynamic studies reveal the role of water molecules in complexes formed between SH2 domains and tyrosyl phosphopeptides.
  Structure, 6, 1141-1151.  
9519305 J.H.Lakey, and E.M.Raggett (1998).
Measuring protein-protein interactions.
  Curr Opin Struct Biol, 8, 119-123.  
9799501 J.M.Bradshaw, and G.Waksman (1998).
Calorimetric investigation of proton linkage by monitoring both the enthalpy and association constant of binding: application to the interaction of the Src SH2 domain with a high-affinity tyrosyl phosphopeptide.
  Biochemistry, 37, 15400-15407.  
9636054 J.M.Bradshaw, R.A.Grucza, J.E.Ladbury, and G.Waksman (1998).
Probing the "two-pronged plug two-holed socket" model for the mechanism of binding of the Src SH2 domain to phosphotyrosyl peptides: a thermodynamic study.
  Biochemistry, 37, 9083-9090.  
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.  
9685372 L.Tong, T.C.Warren, S.Lukas, J.Schembri-King, R.Betageri, J.R.Proudfoot, and S.Jakes (1998).
Carboxymethyl-phenylalanine as a replacement for phosphotyrosine in SH2 domain binding.
  J Biol Chem, 273, 20238-20242.
PDB codes: 1bhf 1bhh
9933909 R.M.Levy, and E.Gallicchio (1998).
Computer simulations with explicit solvent: recent progress in the thermodynamic decomposition of free energies and in modeling electrostatic effects.
  Annu Rev Phys Chem, 49, 531-567.  
9817027 T.K.Sawyer (1998).
Src homology-2 domains: structure, mechanisms, and drug discovery.
  Biopolymers, 47, 243-261.  
9873558 Z.Li, S.L.Yeo, C.J.Pallen, and A.Ganesan (1998).
Solid-phase synthesis of potential protein tyrosine phosphatase inhibitors via the Ugi four-component condensation.
  Bioorg Med Chem Lett, 8, 2443-2446.  
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.

 

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