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Structure of human endo-a-1,2-mannosidase (MANEA), an antiviral host-glycosylation target

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Publication details

JournalProceedings of the National Academy of Sciences of the United States of America
DateAccepted/In press - 28 Sep 2020
DateE-pub ahead of print - 5 Nov 2020
DatePublished (current) - 24 Nov 2020
Issue number47
Number of pages7
Pages (from-to)29595-29601
Early online date5/11/20
Original languageEnglish


Mammalian protein N-linked glycosylation is critical for glycoprotein folding, quality control, trafficking, recognition, and function. N-linked glycans are synthesized from Glc3Man9GlcNAc2precursors that are trimmed and modified in the endoplasmic reticulum (ER) and Golgi apparatus by glycoside hydrolases and glycosyltransferases. Endo-a-1,2-mannosidase (MANEA) is the sole endoacting glycoside hydrolase involved in N-glycan trimming and is located within the Golgi, where it allows ER-escaped glycoproteins to bypass the classical N-glycosylation trimming pathway involving ER glucosidases I and II. There is considerable interest in the use of small molecules that disrupt N-linked glycosylation as therapeutic agents for diseases such as cancer and viral infection. Here we report the structure of the catalytic domain of human MANEA and complexes with substrate-derived inhibitors, which provide insight into dynamic loop movements that occur on substrate binding. We reveal structural features of the human enzyme that explain its substrate preference and the mechanistic basis for catalysis. These structures have inspired the development of new inhibitors that disrupt host protein N-glycan processing of viral glycans and reduce the infectivity of bovine viral diarrhea and dengue viruses in cellular models. These results may contribute to efforts aimed at developing broad-spectrum antiviral agents and help provide a more in-depth understanding of the biology of mammalian glycosylation.

Bibliographical note

Funding Information:
ACKNOWLEDGMENTS. We thank Jon Agirre for assistance with generating a dictionary file for TEW, Eleanor Dodson for assistance with processing the highly anisotropic datasets, Alexandra Males for collecting ITC data with Glc-DMJ, and Mahima Sharma for assisting with supplemental figure production. We also thank Diamond Light Source UK for access to beamlines I03, I04, and I24 (Proposals mx1221, mx12587, and mx18598). Support for this work was provided by the European Research Council (ERC-2012-AdG-32294, “Glycopoise”), the Australian Research Council (DP120101396, FT130100103, and DP180101957), and the Royal Society (a Ken Murray Research Professorship, to G.J.D.).

Publisher Copyright:
© 2020 National Academy of Sciences. All rights reserved.

Copyright 2020 Elsevier B.V., All rights reserved.

    Research areas

  • Antiviral, Enzyme, Glycosylation, Secretory pathway, Structural biology

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