Engineering Diptheria Toxin towards the Development of Therapeutics against Breast Cancer
Final rept. 1 Sep 1996-31 Aug 1999
SALK INST FOR BIOLOGICAL STUDIES LA JOLLA CA
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We have completed the crystal structure determination of diphtheria toxin bound to its normal receptor Louie et al., Molecular Cell, 1, 67-78, 1997. The crystal structure of diphtheria toxin DT complexed 11 with a extracellular fragment of its cell-surface receptor. The toxin receptor is a membrane-bound precursor of a heparin-binding EGF-like growth factor HB-EGF. The structure reveals that a sheet in the receptor-binding domain of DT packs against a beta-sheet of the EGF-like fold. Using a three-dimensional picture as a guide, we have identified key atoms dictating the fit between toxin and receptor and remodify the toxin to target to heregulin, whose overexpression is correlated with the onset of metastatic breast cancer. Future studies will include testing the function of this recombinant toxin in cell culture systems of breast cancer cell lines.
- Medicine and Medical Research