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PDBsum entry 1hcs
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Complex (signal transduction/peptide)
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PDB id
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1hcs
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Solution structure of the human pp60c-Src sh2 domain complexed with a phosphorylated tyrosine pentapeptide.
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Authors
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R.X.Xu,
J.M.Word,
D.G.Davis,
M.J.Rink,
D.H.Willard,
R.T.Gampe.
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Ref.
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Biochemistry, 1995,
34,
2107-2121.
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PubMed id
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Abstract
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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)
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Secondary reference #1
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Title
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Peptide inhibitors of src sh3-Sh2-Phosphoprotein interactions.
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Authors
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T.Gilmer,
M.Rodriguez,
S.Jordan,
R.Crosby,
K.Alligood,
M.Green,
M.Kimery,
C.Wagner,
D.Kinder,
P.Charifson.
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Ref.
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J Biol Chem, 1994,
269,
31711-31719.
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PubMed id
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Secondary reference #2
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Title
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Nuclear magnetic resonance structure of an sh2 domain of phospholipase c-Gamma 1 complexed with a high affinity binding peptide.
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Authors
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S.M.Pascal,
A.U.Singer,
G.Gish,
T.Yamazaki,
S.E.Shoelson,
T.Pawson,
L.E.Kay,
J.D.Forman-Kay.
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Ref.
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Cell, 1994,
77,
461-472.
[DOI no: ]
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PubMed id
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Secondary reference #3
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Title
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Binding of a high affinity phosphotyrosyl peptide to the src sh2 domain: crystal structures of the complexed and peptide-Free forms.
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Authors
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G.Waksman,
S.E.Shoelson,
N.Pant,
D.Cowburn,
J.Kuriyan.
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Ref.
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Cell, 1993,
72,
779-790.
[DOI no: ]
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PubMed id
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Secondary reference #4
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Title
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Recognition of a high-Affinity phosphotyrosyl peptide by the src homology-2 domain of p56lck.
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Authors
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M.J.Eck,
S.E.Shoelson,
S.C.Harrison.
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Ref.
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Nature, 1993,
362,
87-91.
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PubMed id
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Secondary reference #5
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Title
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Human cellular src gene: nucleotide sequence and derived amino acid sequence of the region coding for the carboxy-Terminal two-Thirds of pp60c-Src.
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Authors
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S.K.Anderson,
C.P.Gibbs,
A.Tanaka,
H.J.Kung,
D.J.Fujita.
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Ref.
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Mol Cell Biol, 1985,
5,
1122-1129.
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PubMed id
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