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Assays for Validating Histone Acetyltransferase Inhibitors
Published on: August 6, 2020
La base estructural de la acetilación de proteínas por el coactivador transcripcional p300/CBP
Xin Liu1, Ling Wang, Kehao Zhao
1Program in Gene Expression and Regulation, The Wistar Institute, 3601 Spruce Street, Philadelphia, Pennsylvania 19104, USA.
Nature
|February 15, 2008
Resumen
La estructura de la p300/CBP (CREBBP) histona acetiltransferasa (HAT) revela un mecanismo catalítico único. Este hallazgo ofrece nuevas vías para las terapias epigenéticas dirigidas a enfermedades como el cáncer.
Área de la Ciencia:
- La bioquímica es la bioquímica.
- Biología Estructural Biología estructural.
- La epigenética es la epigenética.
Sus antecedentes:
- p300/CBP (CREBBP) es un coactivador clave de la transcripción y de la histona acetiltransferasa (HAT).
- La actividad desregulada de HAT está implicada en enfermedades, incluido el cáncer.
- Estudios previos sobre el mecanismo y la estructura de p300/CBP arrojaron resultados contradictorios.
Objetivo del estudio:
- Para dilucidar la estructura de alta resolución del dominio p300 HAT.
- Comprender el mecanismo catalítico y la especificidad del sustrato de p300/CBP.
- Proporcionar una base estructural para las mutaciones asociadas a la enfermedad y guiar las estrategias terapéuticas.
Principales métodos:
- Cristalografía de rayos X de alta resolución de un complejo de dominio p300 HAT.
- Análisis bioquímicos y estudios de inhibidores.
- Alineación de secuencias y análisis estructural comparativo.
Principales resultados:
- Se determinó una nueva estructura de dominio heterodímero p300 HAT en complejo con Lys-CoA.
- La estructura revela que la p300/CBP es estructuralmente distinta de otras HAT conocidas.
- Las características novedosas explican la amplia especificidad del sustrato y la preferencia por los residuos básicos.
- Se propone un inusual mecanismo catalítico de "golpe y fuga", distinto de otros HAT.
- Las mutaciones asociadas a la enfermedad se explican fácilmente por la estructura determinada.
Conclusiones:
- La estructura del HAT p300 proporciona una visión sin precedentes de su función y mecanismo.
- Este trabajo aclara la estrategia catalítica única de p300/CBP y las interacciones de sustrato.
- Los hallazgos facilitan el desarrollo de terapias epigenéticas dirigidas para enfermedades relacionadas con p300/CBP.
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