5IEG

Murine endoplasmic reticulum alpha-glucosidase II with N-9'-methoxynonyl-1-deoxynojirimycin.

Summary for 5IEG

• Entry DOI: 10.2210/pdb5ieg/pdb
• Related: 5F0E 5H9O 5HJO 5HJR 5IED 5IEE 5IEF
• Descriptor: Neutral alpha-glucosidase AB, Glucosidase 2 subunit beta, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (10 entities in total)
• Functional Keywords: enzyme glycosyl hydrolase gh31 quality control exoglycosidase, hydrolase, mon-dnj
• Biological source: Mus musculus (Mouse); More
• Cellular location: Endoplasmic reticulum : Q8BHN3 O08795
• Total number of polymer chains: 2
• Total formula weight: 116231.52

Authors

Caputo, A.T.,Roversi, P.,Alonzi, D.S.,Kiappes, J.L.,Zitzmann, N. (deposition date: 2016-02-25, release date: 2016-07-27, Last modification date: 2024-04-24)

Primary citation

Caputo, A.T.,Alonzi, D.S.,Marti, L.,Reca, I.B.,Kiappes, J.L.,Struwe, W.B.,Cross, A.,Basu, S.,Lowe, E.D.,Darlot, B.,Santino, A.,Roversi, P.,Zitzmann, N.
Structures of mammalian ER alpha-glucosidase II capture the binding modes of broad-spectrum iminosugar antivirals.
Proc.Natl.Acad.Sci.USA, 113:E4630-E4638, 2016

PubMed 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.

PubMed: 27462106
DOI: 10.1073/pnas.1604463113

Experimental method

X-RAY DIFFRACTION (1.822 Å)