title: Single-molecule inhibition of human kinesin by adociasulfate-13 and -14 from the sponge Cladocroce aculeata.
abstract: Two merotriterpenoid hydroquinone sulfates designated adociasulfate-13 (1) and adociasulfate-14 (2) were purified from Cladocroce aculeata (Chalinidae) along with adociasulfate-8. All three compounds were found to inhibit microtubule-stimulated ATPase activity of kinesin at 15 µM by blocking both the binding of microtubules and the processive motion of kinesin along microtubules. These findings directly show that substitution of the 5'-sulfate in 1 for a glycolic acid moiety in 2 maintains kinesin inhibition. Nomarski imaging and bead diffusion assays in the presence of adociasulfates showed no signs of either free-floating or bead-bound adociasulfate aggregates. Single-molecule biophysical experiments also suggest that inhibition of kinesin activity does not involve adociasulfate aggregation. Furthermore, both mitotic and nonmitotic kinesins are inhibited by adociasulfates to a significantly different extent. We also report evidence that microtubule binding of nonkinesin microtubule binding domains may be affected by adociasulfates.
authors.affiliation: Departments of Medicinal Chemistry and Physics and Astronomy and Center for Cell and Genome Science, University of Utah, Salt Lake City, UT 84112.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Smith
authors.forename: Weili
authors.initials: W
authors.lastname: Hong
authors.forename: Malcolm M
authors.initials: MM
authors.lastname: Zachariah
authors.forename: Mary Kay
authors.initials: MK
authors.lastname: Harper
authors.forename: Teatulohi K
authors.initials: TK
authors.lastname: Matainaho
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Van Wagoner
authors.forename: Chris M
authors.initials: CM
authors.lastname: Ireland
authors.forename: Michael
authors.initials: M
authors.lastname: Vershinin
mesh_terms: D000818:Animals; D001703:Biophysics; D002463:Cell Membrane Permeability / Q000502:physiology; D055808:Drug Discovery / Q000379:methods / Q000639:trends*; D006801:Humans; D006873:Hydroquinones / Q000378:metabolism / Q000494:pharmacology*; D016547:Kinesins / Q000037:antagonists & inhibitors*; D015394:Molecular Structure; D011161:Porifera / Q000737:chemistry*; D011485:Protein Binding; D013053:Spectrophotometry; D013463:Sulfuric Acid Esters / Q000378:metabolism / Q000494:pharmacology*; D014315:Triterpenes / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D006873:Hydroquinones; D013463:Sulfuric Acid Esters; D014315:Triterpenes; D016547:Kinesins
keywords: mechanism of action; microtubule-based motors; natural products; single-molecule biophysics; terpenes