ArticleProceedings of the National Academy of Sciences of the United States of America2016
Structures of mammalian ER α-glucosidase II capture the binding modes of broad-spectrum iminosugar antivirals.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers.
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Who cites it
39 citing papers in PubMed, 94 citations in OpenAlex.
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- Exploring Small-Molecule Inhibitors of Glucosidase II: Advances, Challenges, and Therapeutic Potential in Cancer and Viral Infection.International journal of molecular sciences · 2025Review
- Development of iminosugar-based glycosidase inhibitors as drug candidates for SARS-CoV-2 virus via molecular modelling and in vitro studies.Journal of enzyme inhibition and medicinal chemistry · 2024Article
- Expanding horizons of iminosugars as broad-spectrum anti-virals: mechanism, efficacy and novel developments.Natural products and bioprospecting · 2024Review
- A quinolin-8-ol sub-millimolar inhibitor of UGGT, the ER glycoprotein folding quality control checkpoint.iScience · 2023Article
- Mutant p53-ENTPD5 control of the calnexin/calreticulin cycle: a druggable target for inhibiting integrin-α5-driven metastasis.Journal of experimental & clinical cancer research : CR · 2023Article
- High-resolution structural-omics of human liver enzymes.Cell reports · 2023Article
- Insight into broad substrate specificity and synergistic contribution of a fungal α-glucosidase in Chinese Nong-flavor daqu.Microbial cell factories · 2023Article
- Simultaneous solving high-resolution structures of various enzymes from human kidney microsomes.Life science alliance · 2023Article
- Midgut membrane protein BmSUH facilitates Bombyx mori nucleopolyhedrovirus oral infection.PLoS pathogens · 2022Article
- The Synthesis and Glycoside Formation of Polyfluorinated Carbohydrates.Chemical reviews · 2022Review
- The primary familial brain calcification-associated protein MYORG is an α-galactosidase with restricted substrate specificity.PLoS biology · 2022Article
- Molecular basis of MHC I quality control in the peptide loading complex.Nature communications · 2022Article
- Structural basis of the strict specificity of a bacterial GH31 α-1,3-glucosidase for nigerooligosaccharides.The Journal of biological chemistry · 2022Article
- Oligomannose-Type Glycan Processing in the Endoplasmic Reticulum and Its Importance in Misfolding Diseases.Biology · 2022Review
- Identification of Cyclic Sulfonamides with anPharmaceuticals (Basel, Switzerland) · 2022Article
- Crystal polymorphism in fragment-based lead discovery of ligands of the catalytic domain of UGGT, the glycoprotein folding quality control checkpoint.Frontiers in molecular biosciences · 2022Article
- Hepatitis C virus E2 envelope glycoprotein produced in Nicotiana benthamiana triggers humoral response with virus-neutralizing activity in vaccinated mice.Plant biotechnology journal · 2021Article
- Clamping, bending, and twisting inter-domain motions in the misfold-recognizing portion of UDP-glucose: Glycoprotein glucosyltransferase.Structure (London, England : 1993) · 2021Article
Corrections and comments
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Authors and funding
13 authors at 3 institutions in 3 countries.
Funding
Abstract
The biosynthesis of enveloped viruses depends heavily on the host cell endoplasmic reticulum (ER) glycoprotein quality control (QC) machinery. This dependency exceeds the dependency of host glycoproteins, offering a window for the targeting of ERQC for the development of broad-spectrum antivirals. We determined small-angle X-ray scattering (SAXS) and crystal structures of the main ERQC enzyme, ER α-glucosidase II (α-GluII; from mouse), alone and in complex with key ligands of its catalytic cycle and antiviral iminosugars, including two that are in clinical trials for the treatment of dengue fever. The SAXS data capture the enzyme's quaternary structure and suggest a conformational rearrangement is needed for the simultaneous binding of a monoglucosylated glycan to both subunits. The X-ray structures with key catalytic cycle intermediates highlight that an insertion between the +1 and +2 subsites contributes to the enzyme's activity and substrate specificity, and reveal that the presence of d-mannose at the +1 subsite renders the acid catalyst less efficient during the cleavage of the monoglucosylated substrate. The complexes with iminosugar antivirals suggest that inhibitors targeting a conserved ring of aromatic residues between the α-GluII +1 and +2 subsites would have increased potency and selectivity, thus providing a template for further rational drug design.
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