2005
DOI: 10.1021/jm049151t
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Design and Biological Evaluation of Linear and Cyclic Phosphopeptide Ligands of the N-Terminal SH2 Domain of Protein Tyrosine Phosphatase SHP-1

Abstract: In an effort to gain further insight into the conformational and topographical requirements for recognition by the N-terminal SH2 domain of protein tyrosine phosphatase SHP-1, we synthesized a series of linear and cyclic peptides derived from the sequence surrounding phosphotyrosine 2267 in the receptor tyrosine kinase Ros (EGLNpYMVL). A molecular modeling approach was used to suggest peptide modifications sterically compatible with the N-SH2-peptide binding groove and possibly enhanced binding affinities comp… Show more

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Cited by 8 publications
(44 citation statements)
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“…The lower efficacy of peptide 2 relative to that of 3 in the competition corresponds to the dissociation constant (K D ) values that were previously obtained for both compounds (0.11 AE 0.01 and 0.21 AE 0.07 mm, respectively). [23] Thus, both cyclic peptides indeed compete directly with the native ligand for binding to the N-SH2 domain, and the smaller ring size in 2 (20 atoms) is favored over 3 (21 atoms). However, according to the results of the competitive phosphatase assay, both peptides inhibited the stimulation of SHP-1 phosphatase activity by Ros pY2267 only at low concentrations (25-50 mm), whereas at higher concentrations a weak activating effect dominated.…”
Section: Competitive Binding Assaymentioning
confidence: 96%
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“…The lower efficacy of peptide 2 relative to that of 3 in the competition corresponds to the dissociation constant (K D ) values that were previously obtained for both compounds (0.11 AE 0.01 and 0.21 AE 0.07 mm, respectively). [23] Thus, both cyclic peptides indeed compete directly with the native ligand for binding to the N-SH2 domain, and the smaller ring size in 2 (20 atoms) is favored over 3 (21 atoms). However, according to the results of the competitive phosphatase assay, both peptides inhibited the stimulation of SHP-1 phosphatase activity by Ros pY2267 only at low concentrations (25-50 mm), whereas at higher concentrations a weak activating effect dominated.…”
Section: Competitive Binding Assaymentioning
confidence: 96%
“…Based on our recent observation that the cyclic peptides 2 and 3 inhibited Ros pY2267-stimulated SHP-1 activity, [23] we hypothesized that both peptides might compete with the native ligand 1 for association with the N-SH2 domain ( Table 2). To test this hypothesis, we assessed the putative competition by binding assays.…”
Section: Competitive Binding Assaymentioning
confidence: 99%
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