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

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    Author
    Sobala, LF; Fernandes, PZ; Hakki, Z; Thompson, AJ; Howe, JD; Hill, M; Zitzmann, N; Davies, S; Stamataki, Z; Butters, TD; ...
    Date
    2020-11-24
    Source Title
    Proceedings of the National Academy of Sciences of USA
    Publisher
    National Academy of Sciences
    University of Melbourne Author/s
    Williams, Spencer
    Affiliation
    School of Chemistry
    Metadata
    Show full item record
    Document Type
    Journal Article
    Citations
    Sobala, L. F., Fernandes, P. Z., Hakki, Z., Thompson, A. J., Howe, J. D., Hill, M., Zitzmann, N., Davies, S., Stamataki, Z., Butters, T. D., Alonzi, D. S., Williams, S. J. & Davies, G. J. (2020). Structure of human endo-alpha-1,2-mannosidase (MANEA), an antiviral host-glycosylation target. Proceedings of the National Academy of Sciences of the United States of America, 117 (47), pp.29595-29601. https://doi.org/10.1073/pnas.2013620117.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/252263
    DOI
    10.1073/pnas.2013620117
    Open Access at PMC
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7703563
    ARC Grant code
    ARC/FT130100103
    ARC/DP120101396
    ARC/DP180101957
    Abstract
    Mammalian protein N-linked glycosylation is critical for glycoprotein folding, quality control, trafficking, recognition, and function. N-linked glycans are synthesized from Glc3Man9GlcNAc2 precursors that are trimmed and modified in the endoplasmic reticulum (ER) and Golgi apparatus by glycoside hydrolases and glycosyltransferases. Endo-α-1,2-mannosidase (MANEA) is the sole endo-acting 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.

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