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Dinámica conformacional en la proteína 2a de unión a la penicilina de Staphylococcus aureus resistente a la
Kiran V Mahasenan1, Rafael Molina2, Renee Bouley1
1Department of Chemistry and Biochemistry, University of Notre Dame , Notre Dame, Indiana 46556, United States.
Journal of the American Chemical Society
|January 19, 2017
Resumen
La proteína 2a de unión a la penicilina (PBP2a) en Staphylococcus aureus utiliza un sitio alostérico para resistir los antibióticos beta-lactámicos. Este mecanismo implica un movimiento de bucle que abre el sitio activo, lo que permite que PBP2a evite la inhibición y conduzca a la resistencia a los antibióticos.
Área de la Ciencia:
- Biología estructural
- Microbiología
- Química medicinal
Sus antecedentes:
- Los antibióticos beta-lactámicos se dirigen a la biosíntesis de la pared celular del peptidoglicano.
- El Staphylococcus aureus utiliza la proteína 2a de unión a la penicilina (PBP2a) para la resistencia.
- PBP2a discrimina contra los beta-lactamas al favorecer los sustratos de peptidoglicano.
Objetivo del estudio:
- Para aclarar la base molecular del mecanismo de resistencia de PBP2a.
- Para entender la regulación alostérica del sitio activo de PBP2a.
- Investigar los conocimientos estructurales sobre la imitación del beta-lactamo y las mutaciones de resistencia.
Principales métodos:
- Cristalografía de rayos X de PBP2a en complejo con tres beta-lactamas (oxacilina, cefepima y ceftazidima).
- Análisis computacionales para correlacionar la unión al sitio alostérico con cambios conformacionales del sitio activo.
- Simulación de las principales etapas catalíticas, incluida la unión al sustrato y la transferencia de acilo.
Principales resultados:
- Las estructuras cristalinas revelaron PBP2a en estados "abiertos" o "parcialmente abiertos" al unirse al beta-lactamo en el sitio alostérico.
- Se identificó un movimiento de bucle adyacente al sitio activo como el conductor de los cambios conformacionales.
- El modelado computacional aclaró la vía de señalización alostérica desde el sitio de unión del efector hasta el sitio activo.
Conclusiones:
- La ocupación del sitio alostérico es crucial para la apertura y función del sitio activo de PBP2a.
- El movimiento del bucle identificado media la comunicación entre los sitios alostéricos y activos.
- La comprensión de estas dinámicas estructurales proporciona una base para combatir la resistencia emergente a PBP2a.
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