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Substrate Engagement and Catalytic Mechanisms of N-Acetylglucosaminyltransferase v

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Publication details

JournalACS Catalysis
DateAccepted/In press - 16 Jul 2020
DateE-pub ahead of print - 16 Jul 2020
DatePublished (current) - 7 Aug 2020
Issue number15
Volume10
Number of pages7
Pages (from-to)8590-8596
Early online date16/07/20
Original languageEnglish

Abstract

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.

Bibliographical note

© 2020 American Chemical Society

    Research areas

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

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