TY  - JOUR
AU  - Sobala, LF
AU  - Fernandes, PZ
AU  - Hakki, Z
AU  - Thompson, AJ
AU  - Howe, JD
AU  - Hill, M
AU  - Zitzmann, N
AU  - Davies, S
AU  - Stamataki, Z
AU  - Butters, TD
AU  - Alonzi, DS
AU  - Williams, SJ
AU  - Davies, GJ
Y2  - 2020/11/26
Y1  - 2020/11/24
SN  - 0027-8424
UR  - http://hdl.handle.net/11343/252263
AB  - 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.
LA  - English
PB  - National Academy of Sciences
T1  - Structure of human endo-alpha-1,2-mannosidase (MANEA), an antiviral host-glycosylation target
DO  - 10.1073/pnas.2013620117
IS  - Proceedings of the National Academy of Sciences of USA
VL  - 117
IS  - 47
SP  - 29595-29601
OP  - DP120101396
OP  - FT130100103
OP  - DP180101957
L1  - /bitstream/handle/11343/252263/2013620117.full.pdf?sequence=1&isAllowed=y
ER  -