This work is being done in collaboration with L. Jolliffe, R.W. Johnson Pharmaceutical Research Institute, and D. Boger, Department of Chemistry. The exciting finding that antagonist peptides dimerize the receptor but do not signal caused us to reevaluate the nature and role of dimerization in signal transduction and cell proliferation. Glycinamide ribonucleotide transformylase and aminoimidazole carboxamide ribonucleotide transformylase are folate-dependent enzymes in the de novo biosynthesis of purines and are potential targets for anticancer and antiinflammatory drugs. Work is in progress on a number of folate and nonfolate inhibitors synthesized in D. Boger's laboratory and cocrystallized with wild-type Escherichia coli glycinamide ribonucleotide transformylase. This project is also a collaboration with S. Benkovic, Pennsylvania State University.
Antibody aldolases with enzymic rates but broader scope.
I.A. The mechanism of an inhibitory antibody on TF-initiated blood coagulation revealed by the crystal structures of human tissue factor, Fab 5G9 and TF.G9 complex. Johnson, D.L., Farrell, F.X., Barbone, F.P., McMahon, F.J., Tullai, J., Hoey, K., Livnah, O., Wrighton, N.C., Middleton, S.A., Loughney, D.A., Stura, E.A., Dower, W.J., Mulcahy, L.S., Wilson, I.A., Jolliffe, L.K. Identification of a 13 amino acid peptide mimetic of erythropoietin and description of amino acids critical for the mimetic activity of EMP1. Wilson, I.A., Garcia, K.C. T-cell receptor structure and TCR complexes.