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PDBsum entry 1lkk
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Complex (tyrosine kinase/peptide) PDB id
1lkk

 

 

 

 

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Contents
Protein chain
105 a.a. *
Ligands
ACE-PTR-GLU-GLU-
ILE
ACE
Waters ×175
* Residue conservation analysis
PDB id:
1lkk
Name: Complex (tyrosine kinase/peptide)
Title: Human p56-lck tyrosine kinase sh2 domain in complex with the phosphotyrosyl peptide ac-ptyr-glu-glu-ile (pyeei peptide)
Structure: Human p56 tyrosine kinase. Chain: a. Fragment: sh2 domain. Engineered: yes. Phosphotyrosyl peptide ac-ptyr-glu-glu-ile. Chain: b. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562.
Biol. unit: Dimer (from PQS)
Resolution:
1.00Å     R-factor:   0.133    
Authors: L.Tong
Key ref:
L.Tong et al. (1996). Crystal structures of the human p56lck SH2 domain in complex with two short phosphotyrosyl peptides at 1.0 A and 1.8 A resolution. J Mol Biol, 256, 601-610. PubMed id: 8604142 DOI: 10.1006/jmbi.1996.0112
Date:
10-Nov-95     Release date:   08-Mar-96    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P24931  (RUBY_DESVH) -  Rubrerythrin from Nitratidesulfovibrio vulgaris (strain ATCC 29579 / DSM 644 / CCUG 34227 / NCIMB 8303 / VKM B-1760 / Hildenborough)
Seq:
Struc: 		191 a.a.
105 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 98 residue positions (black crosses)

 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: 10.1006/jmbi.1996.0112 J Mol Biol 256:601-610 (1996)
PubMed id: 8604142  
 
 
Crystal structures of the human p56lck SH2 domain in complex with two short phosphotyrosyl peptides at 1.0 A and 1.8 A resolution.
L.Tong, T.C.Warren, J.King, R.Betageri, J.Rose, S.Jakes.
 
  ABSTRACT  
 
src homology 2 (SH2) domains are modules of about 100 amino acid residues and bind to phosphotyrosine-containing motifs in a sequence-specific manner. They play important roles in intracellular signal transduction and represent potential targets for pharmacological intervention. The protein tyrosine kinase p56lck is a member of the src family and is involved in T-cell activation. The crystal structure of its SH2 domain with an 11-residue peptide showed that the phosphotyrosine and the Ile residue at the pY + 3 position are recognized by the SH2 domain. We present here the crystal structure of the SH2 domain of human p56lck in complex with the short phosphotyrosyl peptide Ac-pTyr-Glu-Glu-Ile (pYEEI peptide) at 1.0 A resolution. The structural analysis at atomic resolution reveals that residue Arg134 (alphaA2), which interacts with the phosphotyrosine side-chain, is present in two conformations in the complex. The structure at 1.8 A resolution of the complex with the phosphotyrosyl peptide Ac-pTyr-Glu-Glu-Gly (pYEEG peptide), which is 11 fold less potent, shows another binding mode for the pY + 3 residue as well as rearrangements of the side-chain of Arg196 (EF3) and one of the water molecules at the base of the pY + 3 pocket. The structure of the complex with the short pYEEI peptide at atomic resolution represents a good starting point for the design and optimization of new inhibitors. Comparative structural analysis of many different inhibitor complexes will be an important component of this drug discovery process.
 
  Selected figure(s)  
 
Figure 6.
Figure 6. The environment of the phosphotyrosine side-chain in the pYEEI complex. The phosphate group is involved in an intricate network of hydrogen-bonding and charge--charge interactions (thin green lines) with residues in the SH2 domain (thin black lines) and water molecules (red dots). The three terminal oxygen atoms are numbered. The aromatic ring of the phosphotyrosine is situated between the aliphatic portion of Lys182 (bD6) and the guanidinium group of Arg134 (aA2). 		Figure 8.
Figure 8. Superposition of the bound conformations of the pYEEI (thin lines) and the pYEEG (thick lines) peptides.
 
  The above figures are reprinted by permission from Elsevier: J Mol Biol (1996, 256, 601-610) copyright 1996.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
19917655 P.B.Law, and V.Daggett (2010).
The relationship between water bridges and the polyproline II conformation: a large-scale analysis of molecular dynamics simulations and crystal structures.
  Protein Eng Des Sel, 23, 27-33.  
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.  
18767163 W.Gan, and B.Roux (2009).
Binding specificity of SH2 domains: insight from free energy simulations.
  Proteins, 74, 996.  
16245368 F.Nasertorabi, K.Tars, K.Becherer, R.Kodandapani, L.Liljas, K.Vuori, and K.R.Ely (2006).
Molecular basis for regulation of Src by the docking protein p130Cas.
  J Mol Recognit, 19, 30-38.
PDB code: 1x27
17312254 F.Pichierri (2006).
Signal-transducing proteins for nanoelectronics.
  Ann N Y Acad Sci, 1093, 98.  
16283145 D.C.Fry, and L.T.Vassilev (2005).
Targeting protein-protein interactions for cancer therapy.
  J Mol Med, 83, 955-963.  
15867154 H.J.Woo, and B.Roux (2005).
Calculation of absolute protein-ligand binding free energy from computer simulations.
  Proc Natl Acad Sci U S A, 102, 6825-6830.  
11994738 M.B.Yaffe (2002).
Phosphotyrosine-binding domains in signal transduction.
  Nat Rev Mol Cell Biol, 3, 177-186.  
12191610 R.H.Yeh, T.R.Lee, and D.S.Lawrence (2002).
From consensus sequence to high-affinity ligands: acquisition of signaling protein modulators.
  Pharmacol Ther, 93, 179-191.  
11301007 M.A.Young, S.Gonfloni, G.Superti-Furga, B.Roux, and J.Kuriyan (2001).
Dynamic coupling between the SH2 and SH3 domains of c-Src and Hck underlies their inactivation by C-terminal tyrosine phosphorylation.
  Cell, 105, 115-126.  
11266601 P.Minard, M.Scalley-Kim, A.Watters, and D.Baker (2001).
A "loop entropy reduction" phage-display selection for folded amino acid sequences.
  Protein Sci, 10, 129-134.  
11710991 R.Cochrane, R.B.Clark, C.K.Huang, and R.E.Cone (2001).
Differential regulation of T cell receptor-mediated Th1 cell IFN-gamma production and proliferation by divergent cAMP-mediated redox pathways.
  J Interferon Cytokine Res, 21, 797-807.  
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
10329772 E.A.Merritt (1999).
Expanding the model: anisotropic displacement parameters in protein structure refinement.
  Acta Crystallogr D Biol Crystallogr, 55, 1109-1117.  
10476869 J.L.Buchanan, C.B.Vu, T.J.Merry, E.G.Corpuz, S.G.Pradeepan, U.N.Mani, M.Yang, H.R.Plake, V.M.Varkhedkar, B.A.Lynch, I.A.MacNeil, K.A.Loiacono, C.L.Tiong, and D.A.Holt (1999).
Structure-activity relationships of a novel class of Src SH2 inhibitors.
  Bioorg Med Chem Lett, 9, 2359-2364.  
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.  
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
9241420 J.Kuriyan, and D.Cowburn (1997).
Modular peptide recognition domains in eukaryotic signaling.
  Annu Rev Biophys Biomol Struct, 26, 259-288.  
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
9345627 Z.Dauter, V.S.Lamzin, and K.S.Wilson (1997).
The benefits of atomic resolution.
  Curr Opin Struct Biol, 7, 681-688.  
8988011 R.C.Cousins-Wasti, R.H.Ingraham, M.M.Morelock, and C.A.Grygon (1996).
Determination of affinities for lck SH2 binding peptides using a sensitive fluorescence assay: comparison between the pYEEIP and pYQPQP consensus sequences reveals context-dependent binding specificity.
  Biochemistry, 35, 16746-16752.  
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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