Structural basis of new allosteric inhibition in kinesin spindle protein eg5

Hideshi Yokoyama, Jun Ichi Sawada, Shiori Katoh, Kenji Matsuno, Naohisa Ogo, Yoshinobu Ishikawa, Hiroshi Hashimoto, Satoshi Fujii, Akira Asai

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24 Citations (Scopus)


Kinesin spindle protein Eg5 is a target for anticancer therapies, and small molecule inhibitors of its ATPase activity have been developed. We herein report for the first time the crystal structure of and biochemical studies on the Eg5 motor domain in complex with a new type of allosteric inhibitor. The biphenyl-type inhibitor PVZB1194 binds to the α4/α6 allosteric pocket 15 Å from the ATP-binding pocket, which differs from conventional allosteric inhibitors that bind to the allosteric L5/α2/α3 pocket of Eg5. Binding of the inhibitor is involved in the neck-linker conformation and also causes conformational changes around the ATP-binding pocket through Tyr104 to affect the interaction of ATP with the pocket. This structure provides useful information for the development of novel types of allosteric drugs as well as a novel insight into the molecular mechanism responsible for regulating the motor activity of kinesins.

Original languageEnglish
Pages (from-to)1128-1136
Number of pages9
JournalACS Chemical Biology
Issue number4
Publication statusPublished - 17 Apr 2015

Cite this

Yokoyama, H., Sawada, J. I., Katoh, S., Matsuno, K., Ogo, N., Ishikawa, Y., Hashimoto, H., Fujii, S., & Asai, A. (2015). Structural basis of new allosteric inhibition in kinesin spindle protein eg5. ACS Chemical Biology, 10(4), 1128-1136.