1SHD

PEPTIDE INHIBITORS OF SRC SH3-SH2-PHOSPHOPROTEIN INTERACTIONS

Summary for 1SHD

• Entry DOI: 10.2210/pdb1shd/pdb
• Descriptor: C-SRC TYROSINE KINASE SH2 DOMAIN, TRKA RECEPTOR (3 entities in total)
• Functional Keywords: complex(transferase-peptide), complex(transferase-peptide) complex, complex(transferase/peptide)
• Biological source: Homo sapiens (human)
• Cellular location: Cell membrane: P12931
• Total number of polymer chains: 2
• Total formula weight: 13091.59

Authors

Gilmer, T.,Jordan, S. (deposition date: 1994-11-10, release date: 1995-01-26, Last modification date: 2024-10-30)

Primary citation

Gilmer, T.,Rodriguez, M.,Jordan, S.,Crosby, R.,Alligood, K.,Green, M.,Kimery, M.,Wagner, C.,Kinder, D.,Charifson, P.,Hassel, A.M.,Willard, D.,Luther, M.,Rusnak, D.,Sternbach, D.D.,Mehrotra, M.,Peel, M.,Shampine, L.,Davis, R.,Robbins, J.,Patel, I.R.,Kassel, D.,Burkhart, W.,Moyer, M.,Bradshaw, T.,Berman, J.
Peptide inhibitors of src SH3-SH2-phosphoprotein interactions.
J.Biol.Chem., 269:31711-31719, 1994

PubMed Abstract: 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.

PubMed: 7527393

Experimental method

X-RAY DIFFRACTION (2 Å)