Structure of 4'-demethylepipodophyllotoxin in complex with tubulin provides a rationale for drug design.
Biochem Biophys Res Commun
; 493(1): 718-722, 2017 11 04.
Article
em En
| MEDLINE
| ID: mdl-28864414
ABSTRACT
Microtubules consists of αß-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.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Podofilotoxina
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Tubulina (Proteína)
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Desenho de Fármacos
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Moduladores de Tubulina
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Simulação de Acoplamento Molecular
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article