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Interaction of Radicicol with Members of the Heat Shock Protein 90 Family of Molecular Chaperones

Medicine Branch (T.W.S., L.M.N.) National Cancer Institute National Institutes of Health Rockville, Maryland 20850 Pharmaceutical Research Institute Kyowa Hakko Kogyo Co. Ltd. (S.A., T.M., T.A.) Sunto-gun, Shizuoka, Japan 411 Tokyo Research Laboratories (S.S., H.N.) Kyowa Hakko Kogyo Co. Ltd. Machida-shi, Tokyo 194, Japan Laboratory of Ocular Therapeutics (Y.S.L.) National Eye Institute Bethesda, Maryland 20892
Department of Pathology (B.B.S., Y.A.) The University of Chicago Chicago, Illinois 60637
Department of Biochemistry and Molecular Biology (S.F., D.O.T.) Mayo Graduate School Rochester, Minnesota 55905
Department of Microbiology and Immunology (S.V.S.) University of Tennessee Memphis, Tennessee 38163

The Hsp90 family of proteins in mammalian cells consists of Hsp90 and ß, Grp94, and Trap-1 (Hsp75). Radicicol, an antifungal antibiotic that inhibits various signal transduction proteins such as v-src, ras, Raf-1, and mos, was found to bind to Hsp90, thus making it the prototype of a second class of Hsp90 inhibitors, distinct from the chemically unrelated benzoquinone ansamycins. We have used two novel methods to immobilize radicicol, allowing for detailed analyses of drug-protein interactions. Using these two approaches, we have studied binding of the drug to N-terminal Hsp90 point mutants expressed by in vitro translation. The results point to important drug contacts with amino acids inside the N-terminal ATP/ADP-binding pocket region and show subtle differences when compared with geldanamycin binding. Radicicol binds more strongly to Hsp90 than to Grp94, the Hsp90 homolog that resides in the endoplasmic reticulum. In contrast to Hsp90, binding of radicicol to Grp94 requires both the N-terminal ATP/ADP-binding domain as well as the adjacent negatively charged region. Radicicol also specifically binds to yeast Hsp90, Escherichia coli HtpG, and a newly described tumor necrosis factor receptor-interacting protein, Trap-1, with greater homology to bacterial HtpG than to Hsp90. Thus, the radicicol-binding site appears to be specific to and is conserved in all members of the Hsp90 family of molecular chaperones from bacteria to mammals, but is not present in other molecular chaperones with nucleotide-binding domains.

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