TAILIEUCHUNG - Báo cáo khoa học: Dolastatin 15 binds in the vinca domain of tubulin as demonstrated by Hummel–Dreyer chromatography

The antimitotic depsipeptide dolastatin 15 was radiolabeled with tritium in its amino-terminal dolavaline residue. Dolastatin 15, although potently cytotoxic, is a relatively weak inhibitor oftubulin assembly and does not inhibit the binding ofany other ligand to tubulin. The only methodo-logy found to demonstrate an interaction between the dep-sipeptide and tubulin was Hummel–Dreyer equilibrium chromatography on Sephadex G-50 superfine. The average apparent Kd value obtained in these studies was about 30lM, with no difference observed when column size or tubulin concentration was varied | Eur. J. Biochem. 270 3822-3828 2003 FEBS 2003 doi Dolastatin 15 binds in the vinca domain of tubulin as demonstrated by Hummel-Dreyer chromatography Zobeida Cruz-Monserrate1 Jeffrey T. Mullaney2 Patrick G. Harran3 George R. Pettit2 and Ernest Hamel1 1 Screening Technologies Branch Developmental Therapeutics Program Division of Cancer Treatment and Diagnosis National Cancer Institute at Frederick National Institutes of Health Frederick Maryland USA 2Cancer Research Institute and Department of Chemistry and Biochemistry Arizona State University Tempe Arizona USA 3Department of Biochemistry University of Texas Southwestern Medical Center a Dallas Dallas Texas USA The antimitotic depsipeptide dolastatin 15 was radiolabeled with tritium in its amino-terminal dolavaline residue. Dolastatin 15 although potently cytotoxic is a relatively weak inhibitor of tubuiin assembly and does not iihlibit hie binding of sow other iigand to tubulín. The only methodology found to demonstrate an interaction between the dep-sipeptide and tubulin was Hummel-Dreyer equilibrium chromatography on Sephadex G-50 superfine. The average apparent Kd value obtained in these studies was about 30 M with no difference observed when column size or tubulin concentration was varied. This relatively high dissociation constant is consistent with the apparent weak interaction of dolastatin 15 with nihiilm demonstrated indirectly in the assembly assay. We attempted to gain insight into the binding site for dolastatin 15 on tubulin by studying inhibitory effects ofother drugs when the gel filtration column was equilibrated with both 3H dolastatin 15 and a second nonradiolabeled drug. No inhibition was detected with either the colchicine site agent combretastatin A-4 or with an analog of hie nt i im i c marine - lee diazonamide A both the analog and diazonamide A are potent inhibitors oftubulin assembly . Weak inhibition was observed with cemadotin a structural analog .

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