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X-Ray Crystallography to Study the Oligomeric State Transition of the Thermotoga maritima M42 Aminopeptidase TmPep1050
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La interrupción de la oligomerización y la formación de deshidroalanina como mecanismos para la inhibición de la
Malte Gersch1, Roman Kolb, Ferdinand Alte
1Center for Integrated Protein Science at the Department of Chemistry, Institute of Advanced Studies IAS and ‡Center for Integrated Protein Science at the Department of Chemistry, Technische Universität München , Lichtenbergstrasse 4, Garching D-85747, Germany.
Journal of the American Chemical Society
|October 11, 2013
Resumen
Este estudio introduce una nueva estrategia de inhibidor de la proteasa que desmonta los complejos de proteasa, no sólo bloquea los sitios activos. Este nuevo enfoque, demostrado con la proteasa ClpP, conduce a heptámeros inactivos y a la modificación del sitio activo.
Área de la Ciencia:
- La bioquímica es la bioquímica.
- Biología Molecular Biología Molecular
- Descubrimiento de Drogas Descubrimiento de Drogas
Sus antecedentes:
- Los inhibidores de la proteasa son terapias cruciales, y la mayoría se dirigen a los sitios activos.
- El ensamblaje multimérico es vital para la actividad de los objetivos de fármacos clave de las proteasas como el proteosoma y la proteasa del VIH.
- Las estrategias actuales de inhibición implican principalmente el bloqueo del sitio activo o la ocupación del sitio alostérico.
Objetivo del estudio:
- Presentar un nuevo mecanismo de inhibición de la proteasa utilizando moléculas activas dirigidas al sitio que desarman complejos de proteasa.
- Para demostrar la aplicabilidad de este mecanismo en la familia de las proteasas ClpP.
- Para dilucidar los detalles moleculares del proceso de inhibición.
Principales métodos:
- Utilizó pequeñas moléculas dirigidas al sitio activo para atacar a la ClpP proteasa.
- Investigación de la unión de compuestos y su efecto en el ensamblaje del complejo de proteasas.
- Se empleó espectrometría de masas y cristalografía para confirmar las modificaciones estructurales.
- Realizó perfiles de proteínas basados en la actividad en células vivas.
Principales resultados:
- Descubrieron que las moléculas pequeñas pueden desencadenar el desmontaje de la tetradecámara ClpP en heptámeros inactivos.
- Se identificó un nuevo mecanismo que involucra la formación selectiva de deshidroalanina inducida por beta-sultam en la serina del sitio activo.
- Se ha confirmado la formación de deshidroalanina mediante espectrometría de masas y cristalografía.
- Se observó la formación de deshidroalanina en células vivas de Staphylococcus aureus tras el tratamiento con beta-sultam.
Conclusiones:
- Estableció un nuevo paradigma para la inhibición de la proteasa más allá del bloqueo del sitio activo o el control alostérico.
- Demostró que las pequeñas moléculas pueden inducir el desmontaje del complejo proteasa y la inactivación catalítica.
- Destacó el potencial de dirigirse a la integridad del complejo de proteasas para la intervención terapéutica.
- Mostró beta-sultams como agentes efectivos para inducir la formación de deshidroalanina e inhibir la actividad de la proteasa.
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