5MHF

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

Summary for 5MHF

• Entry DOI: 10.2210/pdb5mhf/pdb
• Descriptor: Mannosyl-oligosaccharide glucosidase, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (7 entities in total)
• Functional Keywords: gh63, glucosidase, iminosugar, hydrolase
• Biological source: Mus musculus (Mouse)
• Total number of polymer chains: 4
• Total formula weight: 362041.79

Authors

Hill, J.C.,Caputo, A.T.,Roversi, P.,Zitzmann, N. (deposition date: 2016-11-24, release date: 2017-12-20, Last modification date: 2024-04-24)

Primary citation

Warfield, K.L.,Alonzi, D.S.,Hill, J.C.,Caputo, A.T.,Roversi, P.,Kiappes, J.L.,Sheets, N.,Duchars, M.,Dwek, R.A.,Biggins, J.,Barnard, D.,Shresta, S.,Treston, A.M.,Zitzmann, N.
Targeting Endoplasmic Reticulum alpha-Glucosidase I with a Single-Dose Iminosugar Treatment Protects against Lethal Influenza and Dengue Virus Infections.
J.Med.Chem., 2020

PubMed Abstract: Influenza and dengue viruses present a growing global threat to public health. Both viruses depend on the host endoplasmic reticulum (ER) glycoprotein folding pathway. In 2014, Sadat reported two siblings with a rare genetic defect in ER α-glucosidase I (ER Glu I) who showed resistance to viral infections, identifying ER Glu I as a key antiviral target. Here, we show that a single dose of UV-4B (the hydrochloride salt form of -(9'-methoxynonyl)-1-deoxynojirimycin; MON-DNJ) capable of inhibiting Glu I is sufficient to prevent death in mice infected with lethal viral doses, even when treatment is started as late as 48 h post infection. The first crystal structure of mammalian ER Glu I will constitute the basis for the development of potent and selective inhibitors. Targeting ER Glu I with UV-4B-derived compounds may alter treatment paradigms for acute viral disease through development of a single-dose therapeutic regime.

PubMed: 32227946
DOI: 10.1021/acs.jmedchem.0c00067

Experimental method

X-RAY DIFFRACTION (2.1 Å)