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Using Phage Display to Develop Ubiquitin Variant Modulators for E3 Ligases
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Inhibidores de proteínas semisintéticas diseñados de las enzimas activadoras de Ub/Ubl E1
Xuequan Lu1, Shaun K Olsen, Allan D Capili
1Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Box 422, New York, New York 10065, USA.
Journal of the American Chemical Society
|January 27, 2010
Resumen
Se desarrollaron nuevos inhibidores de proteínas dirigidos a la ubiquitina (Ub) y a los modificadores similares a la ubiquitina (Ubl) que activan las enzimas (E1s). Estas herramientas semisintéticas inhiben selectivamente las enzimas E1, ofreciendo poderosas ideas sobre las vías de ubiquitinación y SUMOilación.
Área de la Ciencia:
- La bioquímica es la bioquímica.
- Biología Molecular Biología Molecular
- Enzimología Enzimología.
Sus antecedentes:
- Las enzimas activadoras de la ubiquitina (Ub) y el modificador similar a la ubiquitina (Ubl) (E1s) son cruciales para la ubiquitinación de proteínas y la SUMOilación.
- Comprender los mecanismos de la enzima E1 es vital para descifrar la señalización celular y los procesos de enfermedad.
Objetivo del estudio:
- Desarrollar nuevos inhibidores de proteínas semisintéticos basados en mecanismos dirigidos a las enzimas E1.
- Investigar los mecanismos catalíticos de las enzimas E1 en la ubiquitinación y la SUMOilación.
- Crear herramientas para investigar las funciones biológicas de las enzimas E1.
Principales métodos:
- Se empleó la ligadura de proteínas expresadas mediada por inteína para generar inhibidores.
- Las proteínas truncadas Ub/Ubl con tioésteres terminales en C fueron ligadas a tripeptidos sintéticos.
- Los inhibidores que contienen grupos de sulfamida o sulfonamida de vinilo fueron diseñados para imitar los intermediarios de reacción o atrapar a los nucleófilos.
Principales resultados:
- SUMO-AMSN y Ub-AMSN inhibieron selectivamente SUMO E1 y Ub E1, respectivamente, de una manera dependiente de la dosis.
- SUMO-AVSN y Ub-AVSN covalentemente entrelazados con SUMO E1 y Ub E1, respectivamente, de una manera dependiente del nucleófilo de la cisteína.
- Los inhibidores desarrollados demostraron una alta selectividad para sus respectivas enzimas E1.
Conclusiones:
- Los inhibidores semisintéticos dirigidos a las enzimas E1 proporcionan herramientas poderosas para estudios mecanicistas.
- Estos inhibidores pueden modular selectivamente las vías de ubiquitinación y SUMOilación.
- Los compuestos desarrollados son valiosos para explorar la función de la enzima E1 y sus funciones biológicas.
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