PMID: 27462106

 

    Legend: Sugar

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

Abstract :
  1. The biosynthesis of enveloped viruses depends heavily on the host cell endoplasmic reticulum ( ER ) glycoprotein quality control (QC) machinery
  2. This dependency exceeds the dependency of host glycoproteins , offering a window for the targeting of ERQC for the development of broad-spectrum antivirals
  3. 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
  4. 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
  5. 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
  6. 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