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Structures of a diverse set of colchicine binding site inhibitors in complex with tubulin provide a rationale for drug discovery.
Wang, Yuxi; Zhang, Hang; Gigant, Benoît; Yu, Yamei; Wu, Yangping; Chen, Xiangzheng; Lai, Qinhuai; Yang, Zhaoya; Chen, Qiang; Yang, Jinliang.
Afiliación
  • Wang Y; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, China.
  • Zhang H; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, China.
  • Gigant B; Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Université Paris-Sud, Gif-sur-Yvette, France.
  • Yu Y; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, China.
  • Wu Y; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, China.
  • Chen X; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, China.
  • Lai Q; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, China.
  • Yang Z; West China School of Pharmacy, Sichuan University, Chengdu, China.
  • Chen Q; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, China.
  • Yang J; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, China.
FEBS J ; 283(1): 102-11, 2016 Jan.
Article en En | MEDLINE | ID: mdl-26462166
UNLABELLED: Microtubules are dynamic assemblies of αß-tubulin heterodimers and have been recognized as highly attractive targets for cancer chemotherapy. A broad range of agents bind to tubulin and interfere with microtubule assembly. Despite having a long history of characterization, colchicine binding site inhibitors (CBSIs) have not yet reached the commercial phase as anti-cancer drugs to date. We determined the structures of tubulin complexed with a set of structurally diverse CBSIs (lexibulin, nocodazole, plinabulin and tivantinib), among which nocodazole and tivantinib are both binary-function inhibitors targeting cancer-related kinases and microtubules simultaneously. High resolution structures revealed the detailed interactions between these ligands and tubulin. Our results showed that the binding modes of the CBSIs were different from previous docking models, highlighting the importance of crystal structure information in structure-based drug design. A real structure-based pharmacophore was proposed to rationalize key common interactions of the CBSIs at the colchicine domain. Our studies provide a solid structural basis for developing new anti-cancer agents for the colchicine binding site. DATABASE: The atomic coordinates and structure factors for tubulin complexed with lexibulin, nocodazole, plinabulin and tivantinib have been deposited in the Protein Data Bank under accession codes 5CA0, 5CA1, 5C8Y and 5CB4, respectively.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Tubulina (Proteína) / Colchicina / Moduladores de Tubulina / Descubrimiento de Drogas / Antineoplásicos Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: FEBS J Asunto de la revista: BIOQUIMICA Año: 2016 Tipo del documento: Article País de afiliación: China Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Tubulina (Proteína) / Colchicina / Moduladores de Tubulina / Descubrimiento de Drogas / Antineoplásicos Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: FEBS J Asunto de la revista: BIOQUIMICA Año: 2016 Tipo del documento: Article País de afiliación: China Pais de publicación: Reino Unido