Tyrosine kinase inhibition: Ligand binding and conformational change in c-Kit and c-Abl.
FEBS Lett
; 583(17): 2899-906, 2009 Sep 03.
Article
em En
| MEDLINE
| ID: mdl-19660459
ABSTRACT
The conformational flexibility exhibited by protein kinases poses an enormous challenge to the design of cancer therapeutics. Additionally the high degree of structural conservation within the kinase superfamily often leads to inhibitors that exhibit little selectivity and substantial cross reactivity. This work investigates the conformational changes that accompany the binding of Gleevec, or imatinib mesylate, to the tyrosine kinases c-Kit and c-Abl. Our analysis is that this fit is driven, at least in part, by the need to exclude water from solvent-exposed backbone hydrogen bonds. Both experimental and molecular modeling studies of the active state inhibitor of the tyrosine kinase c-Abl indicate that solvent exclusion also plays a role in this system.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Piperazinas
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Pirimidinas
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Proteínas Proto-Oncogênicas c-abl
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Estrutura Terciária de Proteína
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Proteínas Proto-Oncogênicas c-kit
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Inibidores de Proteínas Quinases
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Ligantes
Idioma:
En
Ano de publicação:
2009
Tipo de documento:
Article