Reference

Nat Commun 11, 973 (2020). https://doi.org/10.1038/s41467-020-14794-zncomms cover

Authors

García-García, A., Ceballos-Laita, L., Serna, S. et al.

Abstract

Core-fucosylation is an essential biological modification by which a fucose is transferred from GDP-β-L-fucose to the innermost N-acetylglucosamine residue of N-linked glycans. A single human enzyme α1,6-fucosyltransferase (FUT8) is the only enzyme responsible for this modification via the addition of an α-1,6-linked fucose to N-glycans. To date, the details of substrate recognition and catalysis by FUT8 remain unknown. Here, we report the crystal structure of FUT8 complexed with GDP and a biantennary complex N-glycan (G0), which provides insight into both substrate recognition and catalysis. FUT8 follows an SN2 mechanism and deploys a series of loops and an α-helix which all contribute in forming the binding site. An exosite, formed by one of these loops and an SH3 domain, is responsible for the recognition of branched sugars, making contacts specifically to the α1,3 arm GlcNAc, a feature required for catalysis. This information serves as a framework for inhibitor design, and helps to assess its potential as a therapeutic target.

Description

En este artículo se elucidan las bases moleculares de cómo FUT8 reconoce a sus ligandos y como transfiere una unidad de fucosa a los N-glicanos. Esto es muy interesante ya que conocer el mecanismo puede servir para el diseño de fármacos más específicos y potentes contra esta enzima, cuya inhibición permitiría generar anticuerpos con mayor actividad 'ADCC' lo cual es deseable para una mejor actividad terapéutica de los mismos.

 

 202002210840530 hURTADO

REFERENCIA DEL GRUPO INVESTIGADOR

El grupo del investigador ARAID Ramón Hurtado Guerrero que desarrolla su trabajo en el Instituto de Biocomputación y Física de Sistemas Complejos de la Universidad de Zaragoza, lleva más de una década estudiando la unión entre los azúcares y las proteínas que los reconocen para explicar los mecanismos de reacción y poder diseñar inhibidores selectivos que modulen su actividad en procesos patológicos, así como vacunas y tratamientos selectivos.

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