7T8V

Co-crystal structure of Chaetomium glucosidase I with EB-0159

これはPDB形式変換不可エントリーです。

7T8V の概要

• エントリーDOI: 10.2210/pdb7t8v/pdb
• 分子名称: Chaetomium alpha glucosidase, (1S,2S,3R,4S,5S)-1-(hydroxymethyl)-5-[(6-{[2-nitro-4-(1H-1,2,3-triazol-1-yl)phenyl]amino}hexyl)amino]cyclohexane-1,2,3,4-tetrol, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (7 entities in total)
• 機能のキーワード: alpha glucosidase i, hydrolase, inhibitor complex, hydrolase-inhibitor complex, hydrolase/inhibitor
• 由来する生物種: Chaetomium thermophilum var. thermophilum DSM 1495
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 189840.42

構造登録者

Karade, S.S.,Mariuzza, R.A. (登録日: 2021-12-17, 公開日: 2022-05-04, 最終更新日: 2024-10-09)

主引用文献

Karade, S.S.,Kolesnikov, A.,Treston, A.M.,Mariuzza, R.A.
Identification of Endoplasmic Reticulum alpha-Glucosidase I from a Thermophilic Fungus as a Platform for Structure-Guided Antiviral Drug Design.
Biochemistry, 61:822-832, 2022

PubMed Abstract: 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, (), as a robust surrogate for mammalian ER α-GluI and a platform for inhibitor design. Previously annotated only as a hypothetical protein, the protein was validated as a α-glucosidase by comparing its crystal structure to that of mammalian α-GluI, by demonstrating enzymatic activity on the unusual α-d-Glc-(1 → 2)-α-d-Glc-(1 → 3) substrate glycan, and by showing that well-known inhibitors of mammalian α-GluI (1-DNJ, UV-4, UV-5) also inhibit α-GluI. Crystal structures of 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 α-GluI as a surrogate for mammalian α-GluI will accelerate the structure-guided discovery of broad-spectrum antivirals. This study also highlights as a source of thermostable eukaryotic proteins, such as ER α-Glu I, that lack orthologs in bacterial or archaeal thermophiles.

PubMed: 35476408
DOI: 10.1021/acs.biochem.2c00092

実験手法

X-RAY DIFFRACTION (2.3 Å)