Substrate Engagement and Catalytic Mechanisms of N-Acetylglucosaminyltransferase v

John F. Darby, Amelia K. Gilio, Beatriz Piniello, Christian Roth, Elena Blagova, Roderick E. Hubbard, Carme Rovira, Gideon J. Davies*, Liang Wu

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


α-Mannoside β-1,6-N-acetylglucosaminyltransferase V (MGAT5) is a mammalian glycosyltransferase involved in complex N-glycan formation, which strongly drives cancer when overexpressed. Despite intense interest, the catalytic mechanism of MGAT5 is not known in detail, precluding therapeutic exploitation. We solved structures of MGAT5 complexed to glycosyl donor and acceptor ligands, revealing an unforeseen role for donor-induced loop rearrangements in controlling acceptor substrate engagement. QM/MM metadynamics simulations of MGAT5 catalysis highlight the key assisting role of Glu297 and reveal considerable conformational distortions imposed upon the glycosyl donor during transfer. Detailed mechanistic characterization of MGAT5 will aid inhibitor development to correct cancer-associated N-glycosylation.

Original languageEnglish
Pages (from-to)8590-8596
Number of pages7
JournalACS Catalysis
Issue number15
Early online date16 Jul 2020
Publication statusPublished - 7 Aug 2020

Bibliographical note

© 2020 American Chemical Society


  • carbohydrates
  • enzymes
  • glycosyltransferases
  • N-glycosylation
  • quantum mechanics/molecular mechanics

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