The long-term objectives of the research plan are to elucidate the structure-function relationships which control the elongation cycle during protein biosynthesis and to develop pharmacological agents which effectively inhibit growth in infectious bacteria and other rapidly growing cells such as tumors. The primary approach is to study the four EF-Tu complexes formed during the elongation cycle in E. coli by various techniques, including X-ray diffraction analysis. One short-term goal is to elucidate the atomic binding sites of several pharmacological agents on EF-Tu using a highly refined model of trypsin-modified EF-Tu-GDP as the starting model for difference Fourier or molecular replacement calculations. The pharmacological agents which have been cocrystallized with EF-Tu include the chemotherapeutic agent daunorubicin; and the antibiotics, tetracycline, puromycin, aurodox and thiostrepton. Another short-term goal is the structural determination of the EF-Tu-Ts complex. The major significance of this research is that the set of EF-Tu complexes is a good model system for understanding and controlling fundamental mechanisms which not only regulate the elongation cycle but which are mimicked by other normal and abnormal intercellular processes, including certain forms of oncogenesis. The significance of one set of short-term projects is the elucidation of drug binding sites on EF-Tu at the atomic level. Not only will this information contribute to an understanding of the mode of action of these pharmacological agents, but will provide atomic coordinates for the rational drug design for antibiotics and possibly chemotherapeutic agents. The significance of the EF-Tu-Ts project is that the studies will result in an atomic description of (1) a stable catalytic intermediate, (2) a good model system for understanding the GDP/GTP exchange mechanism in sensory and hormone receptor-G protein complexes, (3) and a recognition element in the initiation of RNA synthesis in RNA phages and possibly retroviruses.
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