Structure of human endo-α-1,2-mannosidase (MANEA), an antiviral host-glycosylation target
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 hy...
| Những tác giả chính: | , , , , , , , , , , , , |
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| Định dạng: | Journal article |
| Ngôn ngữ: | English |
| Được phát hành: |
National Academy of Sciences
2020
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| _version_ | 1826280659775127552 |
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| author | Sobala, Ł Fernandes, PZ Hakki, Z Thompson, AJ Howe, JD Hill, M Zitzmann, N Davies, S Stamataki, Z Butters, TD Alonzi, DS Williams, SJ Davies, GJ |
| author_facet | Sobala, Ł Fernandes, PZ Hakki, Z Thompson, AJ Howe, JD Hill, M Zitzmann, N Davies, S Stamataki, Z Butters, TD Alonzi, DS Williams, SJ Davies, GJ |
| author_sort | Sobala, Ł |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-07T00:17:02Z |
| format | Journal article |
| id | oxford-uuid:7b338032-585a-46b4-a4b1-d36ea7803a3c |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T00:17:02Z |
| publishDate | 2020 |
| publisher | National Academy of Sciences |
| record_format | dspace |
| spelling | oxford-uuid:7b338032-585a-46b4-a4b1-d36ea7803a3c2022-03-26T20:49:09ZStructure of human endo-α-1,2-mannosidase (MANEA), an antiviral host-glycosylation targetJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:7b338032-585a-46b4-a4b1-d36ea7803a3cEnglishSymplectic ElementsNational Academy of Sciences2020Sobala, ŁFernandes, PZHakki, ZThompson, AJHowe, JDHill, MZitzmann, NDavies, SStamataki, ZButters, TDAlonzi, DSWilliams, SJDavies, GJMammalian 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. |
| spellingShingle | Sobala, Ł Fernandes, PZ Hakki, Z Thompson, AJ Howe, JD Hill, M Zitzmann, N Davies, S Stamataki, Z Butters, TD Alonzi, DS Williams, SJ Davies, GJ Structure of human endo-α-1,2-mannosidase (MANEA), an antiviral host-glycosylation target |
| title | Structure of human endo-α-1,2-mannosidase (MANEA), an antiviral host-glycosylation target |
| title_full | Structure of human endo-α-1,2-mannosidase (MANEA), an antiviral host-glycosylation target |
| title_fullStr | Structure of human endo-α-1,2-mannosidase (MANEA), an antiviral host-glycosylation target |
| title_full_unstemmed | Structure of human endo-α-1,2-mannosidase (MANEA), an antiviral host-glycosylation target |
| title_short | Structure of human endo-α-1,2-mannosidase (MANEA), an antiviral host-glycosylation target |
| title_sort | structure of human endo α 1 2 mannosidase manea an antiviral host glycosylation target |
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