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Structural basis for the regulation of tubulin by vinblastine

Knossow, Marcel ; Gigant, Benoît ; Wang, Chunguang ; Ravelli, Raimond B. G ; Roussi, Fanny ; Steinmetz, Michel O ; Curmi, Patrick A ; Sobel, André

Nature, 2005-05, Vol.435 (7041), p.519-522 [Periódico revisado por pares]

London: Nature Publishing

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Título:
Structural basis for the regulation of tubulin by vinblastine
Autor: Knossow, Marcel ; Gigant, Benoît ; Wang, Chunguang ; Ravelli, Raimond B. G ; Roussi, Fanny ; Steinmetz, Michel O ; Curmi, Patrick A ; Sobel, André
Assuntos: Binding Sites ; Biochemistry, Molecular Biology ; Biological and medical sciences ; Cancer ; Cellular Biology ; Chemotherapy ; Crystalline structure ; Crystallography, X-Ray ; Dimerization ; Fundamental and applied biological sciences. Psychology ; Hydrophobic and Hydrophilic Interactions ; Kinetics ; Life Sciences ; Microtubule Proteins - chemistry ; Models, Molecular ; Molecular biology ; Molecular biophysics ; Phosphoproteins - chemistry ; Protein Structure, Tertiary ; Stathmin ; Structural Biology ; Structure in molecular biology ; Structure-Activity Relationship ; Tubulin - chemistry ; Tubulin - metabolism ; Vinblastine - chemistry ; Vinblastine - metabolism ; Vinblastine - pharmacology ; X-rays
É parte de: Nature, 2005-05, Vol.435 (7041), p.519-522
Notas: ObjectType-Article-1
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Descrição: Vinblastine is one of several tubulin-targeting Vinca alkaloids that have been responsible for many chemotherapeutic successes since their introduction in the clinic as antitumour drugs. In contrast with the two other classes of small tubulin-binding molecules (Taxol and colchicine), the binding site of vinblastine is largely unknown and the molecular mechanism of this drug has remained elusive. Here we report the X-ray structure of vinblastine bound to tubulin in a complex with the RB3 protein stathmin-like domain (RB3-SLD). Vinblastine introduces a wedge at the interface of two tubulin molecules and thus interferes with tubulin assembly. Together with electron microscopical and biochemical data, the structure explains vinblastine-induced tubulin self-association into spiral aggregates at the expense of microtubule growth. It also shows that vinblastine and the amino-terminal part of RB3-SLD binding sites share a hydrophobic groove on the α-tubulin surface that is located at an intermolecular contact in microtubules. This is an attractive target for drugs designed to perturb microtubule dynamics by interfacial interference, for which tubulin seems ideally suited because of its propensity to self-associate.
Editor: London: Nature Publishing
Idioma: Inglês

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Structural basis for the regulation of tubulin by vinblastine

Knossow, Marcel ; Gigant, Benoît ; Wang, Chunguang ; Ravelli, Raimond B. G ; Roussi, Fanny ; Steinmetz, Michel O ; Curmi, Patrick A ; Sobel, André

London: Nature Publishing

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