Structure of human endo-α-1,2-mannosidase (MANEA), an antiviral host-glycosylation target
| Autor: | Terry D. Butters, Łukasz F. Sobala, Nicole Zitzmann, Andrew J. Thompson, Gideon J. Davies, Dominic S. Alonzi, Michelle L. Hill, Z. Hakki, Spencer J. Williams, Pearl Z. Fernandes, Zania Stamataki, Scott P Davies, J.D. Howe |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Glycan
Glycosylation Biochemistry Antiviral Agents Cell Line Madin Darby Canine Kidney Cells 03 medical and health sciences chemistry.chemical_compound symbols.namesake Dogs Polysaccharides Mannosidases structural biology Animals Humans Glycoside hydrolase Secretory pathway 030304 developmental biology chemistry.chemical_classification 0303 health sciences Secretory Pathway Multidisciplinary biology Endoplasmic reticulum 030302 biochemistry & molecular biology Biological Sciences Dengue Virus Golgi apparatus antiviral 3. Good health carbohydrates (lipids) Chemistry enzyme Structural biology chemistry Physical Sciences biology.protein symbols Bovine Virus Diarrhea-Mucosal Disease Cattle Glycoprotein Glucosidases |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | Significance The glycosylation of proteins is a major protein modification that occurs extensively in eukaryotes. Glycosidases in the secretory pathway that trim N-linked glycans play key roles in protein quality control and in the specific modifications leading to mature glycoproteins. Inhibition of glucosidases in the secretory pathway is a proven therapeutic strategy, that holds great promise in the treatment of viral disease. The enzyme endo-α-1,2-mannosidase (MANEA) provides an alternative processing pathway to evade glucosidase inhibitors. We report the three-dimensional structure of human MANEA and complexes with enzyme inhibitors that we show act as antivirals for bovine viral diarrhea and human dengue viruses. The structure of MANEA will support inhibitor optimization and the development of more potent antivirals. 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. |
| Databáze: | OpenAIRE |
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