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Conocimientos estructurales sobre la absorción del sustrato y la inhibición del transportador humano de creatina

Xinyi Yuan^1,2,3, Jian Yin⁴, Chang Liu⁵

¹Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Hangzhou Normal University, Hangzhou 311121, China.

Proceedings of the National Academy of Sciences of the United States of America

|September 2, 2025

Resumen

El transportador humano de creatina (hCRT) es crucial para la energía y la función cerebral. Los conocimientos estructurales revelan cómo se une la creatina y cómo la RGX202 la bloquea, ofreciendo nuevos objetivos terapéuticos para trastornos neurológicos y cáncer.

Área de la Ciencia:

La bioquímica
Biología estructural
La neurociencia

Sus antecedentes:

La creatina es esencial para la energía celular y la homeostasis de ATP.
El transportador humano de creatina (hCRT) facilita la absorción de la creatina.
Las mutaciones de la hCRT causan trastornos neurológicos, y la hCRT se regula al alza en los tumores.

Objetivo del estudio:

Determinar las estructuras cryo-EM de alta resolución de las TCRH humanas.
Para aclarar los mecanismos de unión de la creatina y el inhibidor RGX202.
Proporcionar una base molecular para el tratamiento de la hCRT en enfermedades.

Principales métodos:

Microscopía criolectrónica de alta resolución (cryo-EM).
Análisis estructural de la hCRT en los estados apo, ligado a la creatina y ligado a RGX202.

Principales resultados:

Determinación de las estructuras cryo-EM de la hCRT en tres estados funcionales.
Se identificó el sitio de unión de la creatina que involucra las hélices transmembrana TM1, TM3, TM6 y TM8.
Se reveló que RGX202 se une al mismo sitio, inhibiendo competitivamente la absorción de creatina.

Conclusiones:

Conocimientos estructurales y mecanicistas sobre la función y la inhibición de la hCRT.
Proporciona una justificación molecular para la orientación de la hCRT en el síndrome de deficiencia de creatina cerebral y el tratamiento del cáncer.

Palabras clave:

Inhibición de la competencia transportador de la creatina humana Absorción del sustrato

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