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Estructura y mecanismo de inhibición del transportador de citrato humano NaCT
David B Sauer1,2, Jinmei Song1,2, Bing Wang3
1Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, NY, USA.
Nature
|February 18, 2021
Resumen
Los investigadores determinaron la estructura del transportador de citrato dependiente de sodio (NaCT) para comprender cómo los inhibidores bloquean la síntesis de ácidos grasos. Esto revela mecanismos para posibles medicamentos contra la obesidad y conocimientos sobre la epilepsia SLC13A5.
Área de la Ciencia:
- La bioquímica
- Biología estructural
- El transporte molecular
Sus antecedentes:
- El citrato es un intermediario metabólico clave y regulador de la síntesis de ácidos grasos.
- La absorción de citrato por las células hepáticas está mediada por el transportador de citrato dependiente de sodio (NaCT), un posible objetivo de fármacos antiobesidad.
- Las mutaciones en SLC13A5, que codifican NaCT, causan epilepsia en los recién nacidos.
Objetivo del estudio:
- Para aclarar la base estructural de la inhibición de NaCT por un inhibidor de molécula pequeña.
- Comprender el mecanismo por el cual el NaCT regula el transporte de citrato.
- Proporcionar un marco estructural para el desarrollo de inhibidores selectivos de NaCT y la comprensión de la epilepsia SLC13A5.
Principales métodos:
- Se utilizó la crio-microscopía electrónica (cryo-EM) para determinar las estructuras del NaCT humano.
- Se obtuvieron estructuras para el NaCT en complejo con citrato y un inhibidor de molécula pequeña.
- Se realizó un análisis comparativo de las estructuras de NaCT con transportadores homólogos.
Principales resultados:
- Las estructuras cryo-EM revelan cómo el inhibidor se une al mismo sitio que el citrato, deteniendo el ciclo de transporte de NaCT.
- La estructura del inhibidor de NaCT explica su selectividad sobre los transportadores de dicarboxilato relacionados.
- Las estructuras proporcionan información sobre cómo las mutaciones en NaCT causan epilepsia.
Conclusiones:
- Las estructuras de NaCT determinadas ofrecen una comprensión molecular de la inhibición del transporte de citrato.
- Estos hallazgos facilitan el diseño de inhibidores NaCT mejorados y selectivos para terapias contra la obesidad.
- Los datos estructurales ayudan a comprender la base molecular de la epilepsia SLC13A5.
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