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Conocimientos estructurales sobre la activación de TMEM175 por moléculas pequeñas

Xuewu Zhu¹, Meixuan Ping², Heng Liu³

¹Zhongshan Institute for Drug Discovery, SIMM, Zhongshan 528400, China; Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.

|August 27, 2025

Resumen

La proteína transmembrana upreguladora 175 (TMEM175) puede tratar la enfermedad de Parkinson mediante la eliminación de la alfa-sinucleína tóxica. Este estudio revela la estructura abierta de TMEM175 con nuevos agonistas, allanando el camino para nuevas terapias de EP.

Área de la Ciencia:

Biología estructural
La neurociencia
Descubrimiento de drogas

Sus antecedentes:

La enfermedad de Parkinson (EP) se caracteriza por la agregación de alfa-sinucleína.
La proteína transmembrana 175 (TMEM175) es un objetivo terapéutico potencial para la EP.
La comprensión de las estructuras agonistas de TMEM175 es clave para desarrollar tratamientos para la EP.

Objetivo del estudio:

Determinación de la estructura criomicroscópica de TMEM175 humano complejo con agonistas.
Para aclarar el mecanismo de activación de TMEM175 por los agonistas.
Evaluar el potencial terapéutico de los agonistas de TMEM175 en el aclaramiento de la alfa-sinucleína y la restauración de la función neuronal.

Principales métodos:

Microscopía cryoelectrónica (cryo-EM) para la determinación estructural.
Resonancia plasmónica de superficie (SPR) y mutagénesis para el análisis de unión.
Simulaciones de endolisomas enteros y dinámicas moleculares para obtener información funcional y mecanicista.

Principales resultados:

Se determinó la primera estructura cryo-EM de TMEM175 humano con los agonistas DCY1020, DCY1040 y TUG-891, revelando una conformación abierta.
Los agonistas DCY1020/1040 se unen en una interfaz de subunidad, induciendo un estado abierto, mejorado sinérgicamente por TUG-891.
Se demostró que estos agonistas facilitan la eliminación de la alfa-sinucleína y restauran la función en las variantes de TMEM175 relacionadas con la EP en las neuronas.

Conclusiones:

El estudio proporciona la base estructural para el agonismo TMEM175, crucial para el descubrimiento de fármacos para la enfermedad de Parkinson.
Los agonistas de TMEM175 muestran potencial para reducir los niveles patológicos de alfa-sinucleína.
Dirigirse a TMEM175 ofrece una estrategia terapéutica prometedora para la enfermedad de Parkinson.

Palabras clave:

La enfermedad de Parkinson Se incluyen los siguientes elementos:agonistas sitio de unión Los lisosomas

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