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Peptide Ligands of pp60c-src SH2 Domains:  A Thermodynamic and Structural Study

Thermodynamic measurements, structural determinations, and molecular computations were applied to a series of peptide ligands of the pp60c-src SH2 domain in an attempt to understand the critical binding determinants for this class of molecules. Isothermal titration calorimetry (ITC) measurements wer...

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Published in:Biochemistry (Easton) 1997-05, Vol.36 (21), p.6283-6293
Main Authors: Charifson, Paul S, Shewchuk, Lisa M, Rocque, Warren, Hummel, Conrad W, Jordan, Steven R, Mohr, Christopher, Pacofsky, Gregory J, Peel, Michael R, Rodriguez, Marc, Sternbach, Daniel D, Consler, Thomas G
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container_issue 21
container_start_page 6283
container_title Biochemistry (Easton)
container_volume 36
creator Charifson, Paul S
Shewchuk, Lisa M
Rocque, Warren
Hummel, Conrad W
Jordan, Steven R
Mohr, Christopher
Pacofsky, Gregory J
Peel, Michael R
Rodriguez, Marc
Sternbach, Daniel D
Consler, Thomas G
description Thermodynamic measurements, structural determinations, and molecular computations were applied to a series of peptide ligands of the pp60c-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 α,α-difluorobenzyl phosphonate analogs of phosphotyrosine retained some binding affinity for the pp60c-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, ΔS 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.
doi_str_mv 10.1021/bi970019n
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Phosphatase-resistant benzylmalonate and α,α-difluorobenzyl phosphonate analogs of phosphotyrosine retained some binding affinity for the pp60c-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, ΔS was 25.6 cal/(mol K) lower than for the nonformylated phosphotyrosine parent. 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title Peptide Ligands of pp60c-src SH2 Domains:  A Thermodynamic and Structural Study
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