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PDBsum entry 1a07
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Complex (transferase/peptide)
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PDB id
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1a07
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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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Peptide ligands of pp60(c-Src) sh2 domains: a thermodynamic and structural study.
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Authors
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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.
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Ref.
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Biochemistry, 1997,
36,
6283-6293.
[DOI no: ]
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PubMed id
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Abstract
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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.
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