Structural insights into the broad-spectrum antiviral target endoplasmic reticulum alpha-glucosidase II
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 t...
| Main Authors: | , , , , , , , , |
|---|---|
| Other Authors: | |
| Format: | Book section |
| Language: | English |
| Published: |
Springer
2018
|
| _version_ | 1797107206853754880 |
|---|---|
| author | Zitzmann, N Caputo, AT Alonzi, DS Kiappes, JL Struwe, WB Cross, A Basu, S Darlot, B Roversi, P |
| author2 | Hilgenfeld, R |
| author_facet | Hilgenfeld, R Zitzmann, N Caputo, AT Alonzi, DS Kiappes, JL Struwe, WB Cross, A Basu, S Darlot, B Roversi, P |
| author_sort | Zitzmann, N |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-07T07:12:43Z |
| format | Book section |
| id | oxford-uuid:b48d5a45-4cc4-4a83-a052-8f90acff6614 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T07:12:43Z |
| publishDate | 2018 |
| publisher | Springer |
| record_format | dspace |
| spelling | oxford-uuid:b48d5a45-4cc4-4a83-a052-8f90acff66142022-07-01T15:11:19ZStructural insights into the broad-spectrum antiviral target endoplasmic reticulum alpha-glucosidase IIBook sectionhttp://purl.org/coar/resource_type/c_1843uuid:b48d5a45-4cc4-4a83-a052-8f90acff6614EnglishSymplectic Elements at OxfordSpringer2018Zitzmann, NCaputo, ATAlonzi, DSKiappes, JLStruwe, WBCross, ABasu, SDarlot, BRoversi, PHilgenfeld, RVasudevan, SGTargeting 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. |
| spellingShingle | Zitzmann, N Caputo, AT Alonzi, DS Kiappes, JL Struwe, WB Cross, A Basu, S Darlot, B Roversi, P Structural insights into the broad-spectrum antiviral target endoplasmic reticulum alpha-glucosidase II |
| title | Structural insights into the broad-spectrum antiviral target endoplasmic reticulum alpha-glucosidase II |
| title_full | Structural insights into the broad-spectrum antiviral target endoplasmic reticulum alpha-glucosidase II |
| title_fullStr | Structural insights into the broad-spectrum antiviral target endoplasmic reticulum alpha-glucosidase II |
| title_full_unstemmed | Structural insights into the broad-spectrum antiviral target endoplasmic reticulum alpha-glucosidase II |
| title_short | Structural insights into the broad-spectrum antiviral target endoplasmic reticulum alpha-glucosidase II |
| title_sort | structural insights into the broad spectrum antiviral target endoplasmic reticulum alpha glucosidase ii |
| work_keys_str_mv | AT zitzmannn structuralinsightsintothebroadspectrumantiviraltargetendoplasmicreticulumalphaglucosidaseii AT caputoat structuralinsightsintothebroadspectrumantiviraltargetendoplasmicreticulumalphaglucosidaseii AT alonzids structuralinsightsintothebroadspectrumantiviraltargetendoplasmicreticulumalphaglucosidaseii AT kiappesjl structuralinsightsintothebroadspectrumantiviraltargetendoplasmicreticulumalphaglucosidaseii AT struwewb structuralinsightsintothebroadspectrumantiviraltargetendoplasmicreticulumalphaglucosidaseii AT crossa structuralinsightsintothebroadspectrumantiviraltargetendoplasmicreticulumalphaglucosidaseii AT basus structuralinsightsintothebroadspectrumantiviraltargetendoplasmicreticulumalphaglucosidaseii AT darlotb structuralinsightsintothebroadspectrumantiviraltargetendoplasmicreticulumalphaglucosidaseii AT roversip structuralinsightsintothebroadspectrumantiviraltargetendoplasmicreticulumalphaglucosidaseii |