Darby, J.F., Gilio, A.K., Piniello, B. et al. (6 more authors) (2020) Substrate engagement and catalytic mechanisms of N-acetylglucosaminyltransferase V. ACS Catalysis, 10 (15). pp. 8590-8596. ISSN 2155-5435
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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2020 American Chemical Society. This is an open access article published under a Creative Commons Attribution (CC-BY) License, (http://pubs.acs.org/page/policy/authorchoice_ccby_termsofuse.html) which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited. |
Keywords: | enzymes; N-glycosylation; carbohydrates; glycosyltransferases; quantum mechanics/molecular mechanics |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Department of Infection and Immunity (Sheffield) |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 05 Nov 2020 15:59 |
Last Modified: | 05 Nov 2020 15:59 |
Status: | Published |
Publisher: | American Chemical Society (ACS) |
Refereed: | Yes |
Identification Number: | 10.1021/acscatal.0c02222 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:167687 |