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Structural Insights into the Broad-Spectrum Antiviral Target Endoplasmic Reticulum Alpha-Glucosidase II

  • Alessandro T. Caputo
  • Dominic S. Alonzi
  • John L. Kiappes
  • Weston B. Struwe
  • Alice Cross
  • Souradeep Basu
  • Benoit Darlot
  • Pietro Roversi
  • Nicole Zitzmann
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1062)

Abstract

Targeting the host-cell endoplasmic reticulum quality control (ERQC) pathway is an effective broad-spectrum antiviral strategy. The two ER resident α-glucosidases whose sequential action permits entry in this pathway are the targets of glucomimetic inhibitors. Knowledge of the molecular details of the ER α-glucosidase II (α-Glu II) structure was limited. We determined crystal structures of a trypsinolytic fragment of murine α-Glu II, alone and in complex with key catalytic cycle ligands, and four different broad-spectrum antiviral iminosugar inhibitors, two of which are currently in clinical trials against dengue fever. The structures highlight novel portions of the enzyme outside its catalytic pocket which contribute to its activity and substrate specificity. These crystal structures and hydrogen-deuterium exchange mass spectrometry of the murine ER alpha glucosidase II heterodimer uncover the quaternary arrangement of the enzyme’s α- and β-subunits, and suggest a conformational rearrangement of ER α-Glu II upon association of the enzyme with client glycoproteins.

Keywords

Endplasmic reticulum quality control Broad spectrum antiviral Glucomimetic inhibitors Hydrogen-deuterium exchange mass spectrometry Antiviral iminosugar 

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Copyright information

© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  • Alessandro T. Caputo
    • 1
  • Dominic S. Alonzi
    • 1
  • John L. Kiappes
    • 1
  • Weston B. Struwe
    • 1
  • Alice Cross
    • 1
  • Souradeep Basu
    • 1
  • Benoit Darlot
    • 1
    • 2
  • Pietro Roversi
    • 1
  • Nicole Zitzmann
    • 1
  1. 1.Department of Biochemistry, Oxford Glycobiology InstituteUniversity of OxfordOxfordUK
  2. 2.Ecole Nationale Supérieure de Chimie de MontpellierMontpellier Cedex 5France

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