Structural basis for substrate specificity and catalysis of α1,6-fucosyltransferase

摘要

Core-fucosylation is an essential biological modification by which a fucose is transferred fromGDP-β-L-fucose to the innermost N-acetylglucosamine residue of N-linked glycans. A singlehuman enzyme α1,6-fucosyltransferase (FUT8) is the only enzyme responsible for thismodification via the addition of an α-1,6-linked fucose to N-glycans. To date, the details ofsubstrate recognition and catalysis by FUT8 remain unknown. Here, we report the crystalstructure of FUT8 complexed with GDP and a biantennary complex N-glycan (G0), whichprovides insight into both substrate recognition and catalysis. FUT8 follows an SN2mechanism and deploys a series of loops and an α-helix which all contribute in forming thebinding site. An exosite, formed by one of these loops and an SH3 domain, is responsible forthe recognition of branched sugars, making contacts specifically to the α1,3 arm GlcNAc, afeature required for catalysis. This information serves as a framework for inhibitor design, andhelps to assess its potential as a therapeutic target.