6ZJ5

Structure of the catalytic domain of human endo-alpha-mannosidase MANEA in complex with GlcDMJ and hexatungstotellurate(VI) TEW

This is a non-PDB format compatible entry.

Summary for 6ZJ5

• Entry DOI: 10.2210/pdb6zj5/pdb
• Descriptor: Glycoprotein endo-alpha-1,2-mannosidase, 4-(2-HYDROXYETHYL)-1-PIPERAZINE ETHANESULFONIC ACID, MAGNESIUM ION, ... (7 entities in total)
• Functional Keywords: golgi, hydrolase, mannosidase, retaining
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 50709.52

Authors

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. (deposition date: 2020-06-27, release date: 2020-12-09, Last modification date: 2024-01-31)

Primary citation

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.
Structure of human endo-alpha-1,2-mannosidase (MANEA), an antiviral host-glycosylation target.
Proc.Natl.Acad.Sci.USA, 117:29595-29601, 2020

PubMed Abstract: Mammalian protein N-linked glycosylation is critical for glycoprotein folding, quality control, trafficking, recognition, and function. N-linked glycans are synthesized from GlcManGlcNAc 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 -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.

PubMed: 33154157
DOI: 10.1073/pnas.2013620117

Experimental method

X-RAY DIFFRACTION (2.269 Å)