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Assessment of Immunologically Relevant Dynamic Tertiary Structural Features of the HIV-1 V3 Loop Crown R2 Sequence by ab initio Folding
Published on: September 16, 2010
La estructura abierta de una proteasa VIH-1 multirresistente se estabiliza mediante contactos de envasado de
Melinda Layten1, Viktor Hornak, Carlos Simmerling
1Program in Molecular and Cellular Biology, Department of Chemistry, and Center for Structural Biology, Stony Brook University, Stony Brook, NY 11794, USA.
Journal of the American Chemical Society
|October 13, 2006
Resumen
La resistencia emergente a los medicamentos en la proteasa del VIH-1 (HIV-PR) amenaza la supervivencia del paciente. Las simulaciones revelan que una estructura cristalina abierta recientemente reportada de un mutante resistente al VIH-PR es inestable y probablemente un artefacto, no explicando los mecanismos de resistencia.
Área de la Ciencia:
- La bioquímica es la bioquímica.
- Biología Estructural Biología estructural.
- Biología computacional Biología computacional.
Sus antecedentes:
- Los inhibidores de la proteasa del VIH-1 (HIV-PR) han mejorado la supervivencia de los pacientes, pero se enfrentan a desafíos por las cepas resistentes a los medicamentos.
- Comprender la dinámica del VIH-PR y las mutaciones de resistencia es crucial para diseñar nuevos inhibidores.
Objetivo del estudio:
- Para investigar la dinámica estructural de la multirresistente (MDR) 769 VIH-PR mutante.
- Evaluar la relevancia de una estructura de cristal abierto recientemente reportada (PDB: 1TW7) de MDR 769 VIH-PR para la resistencia a los medicamentos.
Principales métodos:
- Simulaciones de dinámica molecular del mutante MDR 769 VIH-PR.
- Análisis de la dinámica conformacional de la proteasa en solución.
Principales resultados:
- La estructura cristalina abierta reportada de MDR 769 HIV-PR es inestable en solución, adoptando rápidamente una conformación semiabierta similar a la proteasa no unida de tipo salvaje.
- El estado abierto observado en la estructura cristalina MDR 769 es probablemente un artefacto del empaque de cristales, no una variación de secuencia.
- Esta estructura puede no representar con precisión la entrada del inhibidor o la causa de la resistencia a los medicamentos del VIH-PR.
Conclusiones:
- El bolsillo abierto de unión observado en la estructura cristalina MDR 769 no es representativo del comportamiento de la proteasa en solución.
- La causa de la resistencia a los medicamentos en el aislado MDR 769 puede no estar directamente relacionada con la incapacidad de los inhibidores para inducir el cierre del colgajo, como sugiere esta estructura cristalina.
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