Structure of a benzylidene derivative of 9(10H)-anthracenone in complex with tubulin provides a rationale for drug design
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Collaborative Innovation Center of Biotherapy, Chengdu 610041 (China)
- Department of Respiratory and Critical Care Medicine, West China Hospital of Sichuan University, No. 37, Guo Xue Street, Chengdu, Sichuan 610041 (China)
- Department of Ophthalmology, West China Hospital of Sichuan University, No. 37, Guo Xue Street, Chengdu, Sichuan 610041 (China)
Highlights: • The first crystal structure of an anthracenone family agent complexed with tubulin. • Comparison of the binding mode between different agents reveals the inhibition mechanism. • This structure helps understand the results of the structure-activity-relationship (SAR) studies. Microtubules are composed of αβ-tubulin heterodimers and have been treated as highly attractive targets for antitumor drugs. A broad range of agents bind to tubulin and interfere with microtubule assembly, including colchicine binding site inhibitors (CBSIs). Tubulin Polymerization Inhibitor I (TPI1), a benzylidene derivative of 9(10H)-anthracenone, is a CBSI that inhibits the assembly of microtubules. However, for a long time, the design and development of anthracenone family drugs have been hindered by the lack of structural information of the tubulin-agent complex. Here we report a 2.3 Å crystal structure of tubulin complexed with TPI1, the first structure of anthracenone family agents. This complex structure reveals the interactions between TPI1 and tubulin, and thus provides insights into the development of new anthracenone derivatives targeting the colchicine binding site.
- OSTI ID:
- 23100641
- Journal Information:
- Biochemical and Biophysical Research Communications, Vol. 495, Issue 1; Other Information: Copyright (c) 2017 Elsevier Inc. All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); ISSN 0006-291X
- Country of Publication:
- United States
- Language:
- English
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