2. Academic Validation
  3. Structure of 4'-demethylepipodophyllotoxin in complex with tubulin provides a rationale for drug design

Structure of 4'-demethylepipodophyllotoxin in complex with tubulin provides a rationale for drug design

  • Biochem Biophys Res Commun. 2017 Nov 4;493(1):718-722. doi: 10.1016/j.bbrc.2017.08.125.
Lu Niu 1,  Yuxi Wang 2,  Chengdi Wang 3,  Yanyan Wang 4,  Xiaohua Jiang 1,  Lingling Ma 1,  Chengyong Wu 1,  Yamei Yu 5,  Qiang Chen 6
Affiliations

Affiliations

  • 1 Cancer Center, West China Hospital, Sichuan University, Collaborative Innovation Center of Biotherapy, Chengdu, 610041, PR China.
  • 2 Cancer Center, West China Hospital, Sichuan University, Collaborative Innovation Center of Biotherapy, Chengdu, 610041, PR China; Department of Respiratory and Critical Care Medicine, West China Hospital of Sichuan University, No. 37, Guo Xue Street, Chengdu, Sichuan, 610041, PR China.
  • 3 Department of Respiratory and Critical Care Medicine, West China Hospital of Sichuan University, No. 37, Guo Xue Street, Chengdu, Sichuan, 610041, PR China.
  • 4 Department of Respiratory and Critical Care Medicine, West China Hospital of Sichuan University, No. 37, Guo Xue Street, Chengdu, Sichuan, 610041, PR China; National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 37, Guo Xue Street, Chengdu, Sichuan, 610041, PR China.
  • 5 Cancer Center, West China Hospital, Sichuan University, Collaborative Innovation Center of Biotherapy, Chengdu, 610041, PR China. Electronic address: [email protected].
  • 6 Cancer Center, West China Hospital, Sichuan University, Collaborative Innovation Center of Biotherapy, Chengdu, 610041, PR China. Electronic address: [email protected].
PMID: 28864414 DOI: 10.1016/j.bbrc.2017.08.125
Abstract

Microtubules consists of αβ-tubulin heterodimers and are highly attractive targets for anti-cancer drugs. A broad range of agents have been identified to bind to tubulin and interfere with microtubule assembly, including colchicine binding site inhibitors (CBSIs). Podophyllotoxin is a CBSI that inhibits the assembly of microtubules. However, for a long time, the design and development of podophyllotoxin family drugs have been hindered by the lack of high-resolution structural information of the tubulin-agent complex. We report the first high-resolution (2.8 Å) structure of a podophyllotoxin family agent (4'-demethylepipodophyllotoxin, DMEP) complexed with tubulin and revealed the detailed interactions between DMEP and tubulin. Comparison of this structure and other CBSIs explains previous results of the structure-activity-relationship (SAR) studies, and provides insights into the development of new podophyllotoxin derivatives targeting the colchicine site.

Keywords

Colchicine domain; Crystal structure; Drug design; Podophyllotoxin; Tubulin.

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