دورية أكاديمية
Identification of Endoplasmic Reticulum α-Glucosidase I from a Thermophilic Fungus as a Platform for Structure-Guided Antiviral Drug Design.
| العنوان: | Identification of Endoplasmic Reticulum α-Glucosidase I from a Thermophilic Fungus as a Platform for Structure-Guided Antiviral Drug Design. |
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| المؤلفون: | Karade SS; Institute for Bioscience and Biotechnology Research, University of Maryland, Rockville, Maryland 20850, United States.; Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland 20742, United States., Kolesnikov A; Institute for Bioscience and Biotechnology Research, University of Maryland, Rockville, Maryland 20850, United States.; Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland 20742, United States., Treston AM; Emergent BioSolutions, Gaithersburg, Maryland 20879, United States., Mariuzza RA; Institute for Bioscience and Biotechnology Research, University of Maryland, Rockville, Maryland 20850, United States.; Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland 20742, United States. |
| المصدر: | Biochemistry [Biochemistry] 2022 May 17; Vol. 61 (10), pp. 822-832. Date of Electronic Publication: 2022 Apr 27. |
| نوع المنشور: | Journal Article; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, Non-U.S. Gov't; Research Support, N.I.H., Extramural |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Chemical Society Country of Publication: United States NLM ID: 0370623 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-4995 (Electronic) Linking ISSN: 00062960 NLM ISO Abbreviation: Biochemistry Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Washington, American Chemical Society. |
| مواضيع طبية MeSH: | Viruses*/metabolism , alpha-Glucosidases*/metabolism, Animals ; Antiviral Agents/metabolism ; Antiviral Agents/pharmacology ; Endoplasmic Reticulum/metabolism ; Fungi/metabolism ; Glycoside Hydrolase Inhibitors/pharmacology ; Mammals/metabolism |
| مستخلص: | All viruses depend on host cell proteins for replication. Denying viruses' access to the function of critical host proteins can result in antiviral activity against multiple virus families. In particular, small-molecule drug candidates which inhibit the α-glucosidase enzymes of the endoplasmic reticulum (ER) translation quality control (QC) pathway have demonstrated broad-spectrum antiviral activities and low risk for development of viral resistance. However, antiviral drug discovery focused on the ERQC enzyme α-glucosidase I (α-GluI) has been hampered by difficulties in obtaining crystal structures of complexes with inhibitors. We report here the identification of an orthologous enzyme from a thermophilic fungus, Chaetomium thermophilum ( Ct ), as a robust surrogate for mammalian ER α-GluI and a platform for inhibitor design. Previously annotated only as a hypothetical protein, the Ct protein was validated as a bona fide α-glucosidase by comparing its crystal structure to that of mammalian α-GluI, by demonstrating enzymatic activity on the unusual α-d-Glc p -(1 → 2)-α-d-Glc p -(1 → 3) substrate glycan, and by showing that well-known inhibitors of mammalian α-GluI (1-DNJ, UV-4, UV-5) also inhibit Ct α-GluI. Crystal structures of Ct α-GluI in complex with three such inhibitors (UV-4, UV-5, EB-0159) revealed extensive interactions with all four enzyme subsites and provided insights into the catalytic mechanism. Identification of ER Ct α-GluI as a surrogate for mammalian α-GluI will accelerate the structure-guided discovery of broad-spectrum antivirals. This study also highlights Ct as a source of thermostable eukaryotic proteins, such as ER α-Glu I, that lack orthologs in bacterial or archaeal thermophiles. |
| معلومات مُعتمدة: | P30 GM133894 United States GM NIGMS NIH HHS |
| المشرفين على المادة: | 0 (Antiviral Agents) 0 (Glycoside Hydrolase Inhibitors) EC 3.2.1.- (glucosidase I) EC 3.2.1.20 (alpha-Glucosidases) |
| تواريخ الأحداث: | Date Created: 20220427 Date Completed: 20220519 Latest Revision: 20220624 |
| رمز التحديث: | 20240628 |
| DOI: | 10.1021/acs.biochem.2c00092 |
| PMID: | 35476408 |
| قاعدة البيانات: | MEDLINE |
Find this issue from the American Chemical Society | تدمد: | 1520-4995 |
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| DOI: | 10.1021/acs.biochem.2c00092 |