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La flexibilidad hidrofóbica del núcleo modula la actividad enzimática en la proteasa del VIH-1
Seema Mittal1, Yufeng Cai, Madhavi N L Nalam
1Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
Journal of the American Chemical Society
|February 3, 2012
Resumen
La alteración de la flexibilidad del núcleo hidrofóbico de la proteasa del virus de la inmunodeficiencia humana tipo 1 (VIH-1) afecta significativamente su actividad. Este hallazgo apoya la forma en que las mutaciones pueden afectar la resistencia a los medicamentos mediante la modulación de la función enzimática.
Área de la Ciencia:
- La bioquímica es la bioquímica.
- Biología Estructural Biología estructural.
- Virología Virología.
Sus antecedentes:
- La proteasa del virus de la inmunodeficiencia humana tipo 1 (VIH-1) es vital para la maduración viral.
- El reordenamiento del núcleo hidrofóbico es esencial para la actividad de la proteasa y la resistencia a los medicamentos.
- La flexibilidad de la proteasa puede desempeñar un papel clave en la función de la enzima.
Objetivo del estudio:
- Investigar el papel de la flexibilidad en la actividad de la proteasa del VIH-1.
- Para determinar si la alteración de la flexibilidad afecta la función enzimática y la resistencia a los fármacos.
Principales métodos:
- Enlaces de disulfuro diseñados en regiones flexibles de la proteasa del VIH-1.
- Se confirmó la formación de enlaces disulfuro utilizando estructuras cristalinas, alquilación y espectrometría de masas.
- Evaluó la actividad enzimática en estados oxidados y reducidos y realizó simulaciones de dinámica molecular.
Principales resultados:
- El enlace cruzado de disulfuro redujo drásticamente la actividad de la proteasa.
- La actividad enzimática se restauró tras la reducción de los enlaces disulfuro.
- Las simulaciones mostraron dinámicas alteradas propagadas desde el enlace disulfuro diseñado.
Conclusiones:
- La flexibilidad alterada en el núcleo hidrofóbico modula la actividad de la proteasa del VIH-1.
- Las mutaciones distantes pueden conferir resistencia a los medicamentos al alterar la flexibilidad de las enzimas y el equilibrio de actividad.
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