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

Journal Article · Fri May 09 04:00:00 EDT 2014 · Biochemical and Biophysical Research Communications

DOI:https://doi.org/10.1016/J.BBRC.2014.04.023· OSTI ID:22416425

Sun, Linlin ^[1]; Sun, Xiaodong; Xie, Songbo; Yu, Haiyang ^[2]; Zhong, Diansheng ^[1]

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1. Lung Cancer Institute, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin 300052 (China)
2. Department of Genetics and Cell Biology, College of Life Sciences, Nankai University, 94 Weijin Road, Tianjin 300071 (China)

Highlights: • DIMEN displays higher anti-proliferative activity than enastron. • DIMEN induced mitotic arrest and apoptosis more significantly than enastron. • DIMEN blocked the conformational change of ADP-binding pocket more effectively. • DIMEN hindered ADP release more potently than enastron. - 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.

• OSTI ID: 22416425
• Journal Information: Biochemical and Biophysical Research Communications, Journal Name: Biochemical and Biophysical Research Communications Journal Issue: 3 Vol. 447; ISSN BBRCA9; ISSN 0006-291X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ADP
AFFINITY
APOPTOSIS
ATP
CELL PROLIFERATION
COMPARATIVE EVALUATIONS
CONFORMATIONAL CHANGES
LUNGS
MICROTUBULES
MOLECULES
NEOPLASMS
PANCREAS