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A Competent Hepatocyte Model Examining Hepatitis B Virus Entry through Sodium Taurocholate Cotransporting Polypeptide as a Therapeutic Target
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Estructura del transportador de ácido biliar y del receptor del VHB NTCP
Jinta Asami1, Kanako Terakado Kimura2, Yoko Fujita-Fujiharu3,4,5
1Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
Nature
|May 17, 2022
Resumen
El virus de la hepatitis B (VHB) utiliza glicoproteínas de envoltura grande (LHB) para unirse a los receptores de las células huésped. Este estudio revela la base estructural de la entrada de HBV a través de NTCP, proporcionando un marco para comprender las interacciones virus-huésped.
Área de la Ciencia:
- Biología estructural
- Virología
- Hepatología
Sus antecedentes:
- La infección crónica por el virus de la hepatitis B (VHB) afecta a más de 290 millones de personas en todo el mundo, lo que lleva a la cirrosis y al cáncer de hígado.
- La entrada del VHB en los hepatocitos requiere una interacción entre las glicoproteínas virales de envoltura grande (LHBs) y el polipéptido co-transportador de taurocolato de sodio (NTCP) del receptor huésped.
- Los mecanismos moleculares precisos que subyacen a la interacción HBV-NTCP siguen siendo poco conocidos.
Objetivo del estudio:
- Para aclarar la base estructural de la interacción entre el VHB y su receptor de entrada en la célula huésped, NTCP.
- Comprender el mecanismo de transporte de ácido biliar dependiente del sodio por NTCP.
- Proporcionar un marco estructural para el desarrollo de nuevas estrategias antivirales contra el VHB.
Principales métodos:
- Se utilizó la criomicroscopia electrónica (cryo-EM) para determinar las estructuras de los NTCP en humanos, bovinos y ratas en estados apo y pre-S1.
- Se realizaron ensayos de mutación y transporte para validar el modo de unión propuesto y las implicaciones funcionales.
- El análisis estructural se integró con los datos bioquímicos para interpretar las mutaciones insusceptibles del VHB en el NTCP.
Principales resultados:
- Las estructuras cryo-EM revelaron un túnel que abarca la membrana en NTCP, lo que sugiere una vía de transporte de sustrato.
- La estructura del NTCP humano unido al dominio preS1 de LHBs indicó que preS1 y el sustrato de NTCP compiten por el mismo sitio de unión en la abertura extracelular del túnel.
- El análisis de las interacciones preS1-NTCP proporcionó información mecanicista sobre las mutaciones naturales que confieren resistencia al VHB.
Conclusiones:
- El estudio proporciona estructuras de alta resolución de NTCP, detallando su mecanismo de transporte e interacción con el VHB.
- Se ha establecido un marco estructural para el reconocimiento del VHB por el NTCP, que aclara la base molecular de la entrada viral.
- Estos hallazgos ofrecen una comprensión mecanicista del transporte de ácido biliar y allanan el camino para terapias dirigidas al VHB.
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