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Nat Chem Biol September 1, 2006; 2 (9): 480-5.
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Allosteric inhibition of kinesin-5 modulates its processive directional motility.

Kwok BH , Kapitein LC , Kim JH , Peterman EJ , Schmidt CF , Kapoor TM .

Small-molecule inhibitors of kinesin-5 (refs. 1-3), a protein essential for eukaryotic cell division, represent alternatives to antimitotic agents that target tubulin. While tubulin is needed for multiple intracellular processes, the known functions of kinesin-5 are limited to dividing cells, making it likely that kinesin-5 inhibitors would have fewer side effects than do tubulin-targeting drugs. Kinesin-5 inhibitors, such as monastrol, act through poorly understood allosteric mechanisms, not competing with ATP binding. Moreover, the microscopic mechanism of full-length kinesin-5 motility is not known. Here we characterize the motile properties and allosteric inhibition of Eg5, a vertebrate kinesin-5, using a GFP fusion protein in single-molecule fluorescence assays. We find that Eg5 is a processive kinesin whose motility includes, in addition to ATP-dependent directional motion, a diffusive component not requiring ATP hydrolysis. Monastrol suppresses the directional processive motility of microtubule-bound Eg5. These data on Eg5''s allosteric inhibition will impact these inhibitors'' use as probes and development as chemotherapeutic agents.

PubMed ID: 16892050
Article link: Nat Chem Biol
Grant support: [+]

Species referenced: Xenopus laevis
Genes referenced: kif11