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Reconocimiento de histonas y análisis estructural a gran escala de la familia de bromodomaínas humanas
Panagis Filippakopoulos1, Sarah Picaud, Maria Mangos
1Nuffield Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7LD, UK. panagis.filippakopoulos@sgc.ox.ac.uk
Cell
|April 3, 2012
Resumen
Los Bromodomains (BRDs) reconocen las marcas epigenéticas. Este estudio revela características estructurales conservadas y únicas en todas las familias de BRD, descubriendo nuevos sustratos y cómo las modificaciones influyen en la unión para el diseño de fármacos.
Área de la Ciencia:
- Biología estructural Biología estructural.
- La epigenética es la epigenética.
- Las interacciones proteína-proteína.
Sus antecedentes:
- Los bromodomaines (BRDs) son lectores epigenéticos cruciales que se unen a los residuos de lisina acetilada.
- El genoma humano contiene 61 BRD, clasificados en ocho familias basadas en similitudes estructurales y de secuencia.
- Comprender la estructura y función de BRD es vital para la investigación epigenética y el desarrollo terapéutico.
Objetivo del estudio:
- Presentar estructuras cristalinas de alta resolución de 29 diversos Bromodomains (BRDs) de las ocho familias.
- Para analizar las características estructurales conservadas y específicas de la familia que rigen el reconocimiento del sustrato dependiente de la acetilación.
- Identificar nuevos sustratos de BRD y comprender el papel de las modificaciones post-traducionales en la unión de BRD.
Principales métodos:
- Cristalografía de rayos X para determinar 29 estructuras BRD de alta resolución.
- Análisis estructural interfamiliar para identificar características conservadas y únicas.
- Cribado sistemático de más de 30 BRDs contra matrices de histona y péptido.
Principales resultados:
- Conocimientos estructurales detallados de las ocho familias de BRD, destacando características para el reconocimiento de sustratos específicos.
- Identificación de nuevos sustratos de BRD y demostración de cómo la acetilación y fosforilación flanqueantes influyen en la unión.
- Elucidación de un mecanismo estructural para el reconocimiento de péptidos diacetilados por BRD4.
Conclusiones:
- Las estructuras presentadas proporcionan un recurso integral para la comprensión de las interacciones BRD-marcas epigenéticas.
- El reconocimiento de BRD está influenciado por combinaciones de modificaciones post-traduccionales, no solo por eventos de acetilación individuales.
- Estos hallazgos sientan las bases para el diseño de fármacos basados en la estructura dirigidos a inhibidores específicos de BRD.
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