1shd

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spinqualitylabelsall models 1shd, resolution 2.0Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

PEPTIDE INHIBITORS OF SRC SH3-SH2-PHOSPHOPROTEIN INTERACTIONS

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

Overview

Activated pp60c-src has been implicated in a number of human malignancies, including colon carcinoma and breast adenocarcinoma. Association of the, src SH2 domain with tyrosine-phosphorylated proteins plays a role in, src-mediated signal transduction. Inhibitors of src SH2, domain-phosphoprotein interactions are, thus, of great interest in, defining the role(s) of src in signal transduction pathways. To facilitate, such studies, an enzyme-linked immunosorbent assay (ELISA) was developed, to detect inhibitors of src SH2-phosphoprotein interactions. This assay, measures inhibition of binding of a fusion construct (glutathione, S-transferase src SH3-SH2) with autophosphorylated epidermal growth factor, receptor tyrosine kinase domain. Activities of phosphopeptide segments, derived from potential src SH2 cognate phosphoprotein partners were, determined, with the focal adhesion kinase-derived segment VSETDDY*AEIIDE, yielding the highest inhibitory activity. Structure activity studies, starting from acetyl (Ac)-Y*EEIE have identified Ac-Y*Y*Y*IE as the most, active compound screened in the ELISA. This compound is at least 20-fold, more active than the parent peptide Ac-Y*EEIE. A high resolution (2 A), crystal structure of human src SH2 complexed with Ac-Y*EEIE was obtained, and provided a useful framework for understanding the structure-activity, relationships. Additionally, Ac-Y*EEIE was able to block interactions, between src and its cellular phosphoprotein partners in vanadate-treated, cell lysates from MDA-MB-468 breast carcinoma cells. However, it is unable, to abrogate proliferation of MDA-MB-468 cells in culture, presumably, because of poor cell penetration and/or lability of the phosphate group on, tyrosine.

Disease

Known disease associated with this structure: Colon cancer, advanced OMIM:[190090]

About this Structure

1SHD is a Single protein structure of sequence from Homo sapiens with PO3 and ACE as ligands. Full crystallographic information is available from OCA.

Reference

Peptide inhibitors of src SH3-SH2-phosphoprotein interactions., Gilmer T, Rodriguez M, Jordan S, Crosby R, Alligood K, Green M, Kimery M, Wagner C, Kinder D, Charifson P, et al., J Biol Chem. 1994 Dec 16;269(50):31711-9. PMID:7527393

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