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dc.contributor.authorSobala, LF
dc.contributor.authorFernandes, PZ
dc.contributor.authorHakki, Z
dc.contributor.authorThompson, AJ
dc.contributor.authorHowe, JD
dc.contributor.authorHill, M
dc.contributor.authorZitzmann, N
dc.contributor.authorDavies, S
dc.contributor.authorStamataki, Z
dc.contributor.authorButters, TD
dc.contributor.authorAlonzi, DS
dc.contributor.authorWilliams, SJ
dc.contributor.authorDavies, GJ
dc.date.accessioned2020-11-26T23:32:45Z
dc.date.available2020-11-26T23:32:45Z
dc.date.issued2020-11-24
dc.identifierpii: 2013620117
dc.identifier.citationSobala, 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.
dc.identifier.issn0027-8424
dc.identifier.urihttp://hdl.handle.net/11343/252263
dc.description.abstractMammalian 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.
dc.languageEnglish
dc.publisherNational Academy of Sciences
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0
dc.titleStructure of human endo-alpha-1,2-mannosidase (MANEA), an antiviral host-glycosylation target
dc.typeJournal Article
dc.identifier.doi10.1073/pnas.2013620117
melbourne.affiliation.departmentSchool of Chemistry
melbourne.source.titleProceedings of the National Academy of Sciences of USA
melbourne.source.volume117
melbourne.source.issue47
melbourne.source.pages29595-29601
melbourne.identifier.arcDP120101396
melbourne.identifier.arcFT130100103
melbourne.identifier.arcDP180101957
dc.rights.licenseCC BY-NC-ND
melbourne.elementsid1478845
melbourne.openaccess.pmchttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC7703563
melbourne.contributor.authorWilliams, Spencer
melbourne.contributor.authorFernandes, Pearl
dc.identifier.eissn1091-6490
melbourne.identifier.fundernameidAustralian Research Council, FT130100103
melbourne.identifier.fundernameidAUST RESEARCH COUNCIL, DP120101396
melbourne.identifier.fundernameidAustralian Research Council, DP180101957
melbourne.accessrightsOpen Access


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