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Inhibidores químicos potentes, reversibles y específicos de la biogénesis de los ribosomas eucariotas

Shigehiro A Kawashima¹, Zhen Chen², Yuki Aoi³

¹The University of Tokyo, Graduate School of Pharmaceutical Sciences, Tokyo 1130033, Japan; Laboratory of Chemistry and Cell Biology, The Rockefeller University, New York, NY 10065, USA.

|September 27, 2016

Resumen

Los investigadores desarrollaron nuevos inhibidores basados en triazinoindoles, ribozinoindoles (Rbins), para estudiar el ensamblaje de los ribosomas eucariotas. Estas potentes sondas apuntan a la Midasina, revelando su papel crucial en la formación de precursores de las subunidades 60S del ribosoma.

Área de la Ciencia:

Biología molecular
La bioquímica
Biología celular

Sus antecedentes:

La biogénesis del ribosoma es esencial para la síntesis de proteínas en eucariotas.
Los inhibidores químicos existentes carecen de especificidad para analizar la dinámica de ensamblaje de ribosomas.
Se necesitan nuevas sondas químicas para investigar el ensamblaje de los ribosomas eucariotas.

Objetivo del estudio:

Descubrir y validar sondas químicas para el estudio de la biogénesis de los ribosomas eucariotas.
Para identificar el objetivo molecular de nuevos inhibidores.
Para aclarar el papel de la Midasina en el ensamblaje de ribosomas.

Principales métodos:

Cribado químico y genético en levaduras de fisión.
Pruebas bioquímicas con proteínas recombinantes.
Análisis de las mutaciones de sensibilidad y resistencia al inhibidor.

Principales resultados:

Descubrimiento de ribozinoindoles (Rbins), inhibidores potentes y reversibles de la biogénesis de los ribosomas.
Identificación de la Midasina, una ATPasa AAA+, como objetivo fisiológico de las Rbins.
Descubriendo el papel esencial de Midasin en el ensamblaje de las partículas Nsa1, precursores de la subunidad ribosómica 60S.

Conclusiones:

Las ribozinoindolas (Rbins) son potentes sondas químicas para el ensamblaje de los ribosomas eucariotas.
La midasina juega un papel crítico en las primeras etapas de la biogénesis de la subunidad ribosómica 60S.
Las Rbins permiten una manipulación aguda de la función de Midasin para estudios dinámicos del ensamblaje de ribosomas.

Palabras clave:

Proteínas AAA Midasina y sus derivados Schizosaccharomyces pombe y sus derivados genética química Inhibidores químicos Cuadro químico levadura de fisión Biogénesis de los ribosomas

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