Significant decrease of ADP release rate underlies the potent activity of dimethylenastron to inhibit mitotic kinesin Eg5 and cancer cell proliferation.

Abstract	Eg5 is a mitotic kinesin that plays a crucial role in the formation of bipolar mitotic spindles, by hydrolyzing ATP to push apart anti-parallel microtubules. Dimethylenastron is potent specific small molecule inhibitor of Eg5. The mechanism by which dimethylenastron inhibits Eg5 function remains unclear. By comparing with enastron, here we report that dimethylenastron prevents the growth of pancreatic and lung cancer cells more effectively, by halting mitotic progression and triggering apoptosis. We analyze their interactions with ADP-bound Eg5 crystal structure, and find that dimethylenastron binds Eg5 motor domain with higher affinity. In addition, dimethylenastron allosterically blocks the conformational change of the "sandwich"-like ADP-binding pocket more effectively. We subsequently use biochemical approach to reveal that dimethylenastron slows ADP release more significantly than enastron. These data thus provide biological, structural and mechanistic insights into the potent inhibitory activity of dimethylenastron.
Authors	Linlin Sun, Xiaodong Sun, Songbo Xie, Haiyang Yu, Diansheng Zhong
Journal	Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 447 Issue 3 Pg. 465-70 (May 09 2014) ISSN: 1090-2104 [Electronic] United States
PMID	24732354 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright	Copyright © 2014 Elsevier Inc. All rights reserved.
Chemical References	Antineoplastic Agents KIF11 protein, human Quinazolines Thiones dimethylenastron enastron Adenosine Diphosphate Adenosine Triphosphatases Kinesins
Topics	Adenosine Diphosphate (metabolism) Adenosine Triphosphatases (antagonists & inhibitors, chemistry) Antineoplastic Agents (pharmacology) Cell Line, Tumor Cell Proliferation (drug effects) Crystallography, X-Ray Humans Kinesins (antagonists & inhibitors, chemistry) Mitosis (drug effects) Protein Binding (drug effects) Protein Conformation (drug effects) Protein Structure, Tertiary Quinazolines (pharmacology) Thiones (pharmacology)

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