Structures of mammalian ER α-glucosidase II capture the binding modes of broad-spectrum iminosugar antivirals

Proc Natl Acad Sci U S A. 2016 Aug 9;113(32):E4630-8. doi: 10.1073/pnas.1604463113. Epub 2016 Jul 26.


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.

Keywords: ER α-glucosidase II; broad-spectrum antiviral; eukaryotic secretion; glycoprotein folding; iminosugar.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiviral Agents / pharmacology*
  • Catalysis
  • Crystallography, X-Ray
  • Endoplasmic Reticulum / enzymology*
  • Glycoside Hydrolase Inhibitors / pharmacology*
  • Mice
  • Protein Conformation
  • Protein Subunits
  • Scattering, Small Angle
  • Substrate Specificity
  • alpha-Glucosidases / chemistry*


  • Antiviral Agents
  • Glycoside Hydrolase Inhibitors
  • Protein Subunits
  • alpha-Glucosidases

Associated data

  • PDB/5F0E
  • PDB/5H9O
  • PDB/5HJO
  • PDB/5HJR
  • PDB/5IED
  • PDB/5IEE
  • PDB/5IEF
  • PDB/5IEG