Inhibition of kinesin motor proteins by adociasulfate-2

Khalilah G. Reddie, Donald R. Roberts, Timothy M. Dore

Research output: Contribution to journalArticle

Abstract

Kinesin motor proteins are involved in cell division and intracellular transport of vesicles and organelles, and as such, they play a role in neurological disease, cancer, and developmental disorders. Inhibitors of kinesin would be valuable as probes of cell physiology and as potential therapeutics. Adociasulfate-2 (AS-2) is the only known natural product inhibitor of kinesins, but its mechanism of action is unknown. We utilized kinetic studies, dynamic light scattering, and transmission electron microscopy to investigate the inhibitory action of AS-2. Our data suggest that AS-2 is not a classical 1:1 inhibitor. Instead, a rodlike aggregate that mimics microtubules is complexed with kinesin and inhibits its ATPase activity. An intriguing implication of this hypothesis is that aggregates of a chiral natural product can have interesting and biologically relevant properties. This mode of action might represent one way in which a small molecule can disrupt a protein-protein interaction.

Original languageEnglish (US)
Pages (from-to)4857-4860
Number of pages4
JournalJournal of Medicinal Chemistry
Volume49
Issue number16
DOIs
StatePublished - Aug 10 2006

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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