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

DOI: 10.1073/pnas.1604463113 DOI Help

Authors: Alessandro T. Caputo (Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford) , Dominic S. Alonzi (Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford) , Lucia Marti (Institute of Sciences of Food Production, Consiglio Nazionale delle Ricerche Unit of Lecce) , Ida-barbara Reca (Institute of Sciences of Food Production, Consiglio Nazionale delle Ricerche Unit of Lecce) , John Kiappes (University of Oxford) , Weston B. Struwe (University of Oxford) , Alice Cross (Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, Diamond Light Source) , Souradeep Basu (Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford) , Ed Lowe (University of Oxford) , Benoit Darlot (Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford; Ecole Nationale Supérieure de Chimie de Montpellie, Diamond Light Source) , Angelo Santino (Institute of Sciences of Food Production, Consiglio Nazionale delle Ricerche Unit of Lecce) , Pietro Roversi (Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, Diamond Light Source) , Nicole Zitzmann (Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, Diamond Light Source)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Proceedings Of The National Academy Of Sciences , VOL 113 , PAGES E4630 - E4638

State: Published (Approved)
Published: August 2016
Diamond Proposal Number(s): 9306

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.

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

Subject Areas: Chemistry, Biology and Bio-materials, Medicine


Instruments: I02-Macromolecular Crystallography , I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography

Other Facilities: ESRF