期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 110, 期 47, 页码 18880-18885出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1314132110
关键词
single-molecule biophysics; natural products; mechanism of action; microtubule-based motors; terpenes
资金
- National Institutes of Health (NIH) through Fogarty International Center [ICBG 5U01T006671]
- INOVA
- NIH [RR06262]
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 mu M by blocking both the binding ofmicrotubules 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.
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