8JBO

Crystal structure of TxGH116 from Thermoanaerobacterium xylanolyticum with isofagomine

8JBO の概要

• エントリーDOI: 10.2210/pdb8jbo/pdb
• 関連するPDBエントリー: 5BVU 5BX2 5BX3 5BX4 5BX5
• 分子名称: Glucosylceramidase, 5-HYDROXYMETHYL-3,4-DIHYDROXYPIPERIDINE, CALCIUM ION, ... (6 entities in total)
• 機能のキーワード: txgh116, beta-glucosidase, acid/base mutant, thermoanaerobacterium xylanolyticum, cellobiose, hydrolase
• 由来する生物種: Thermoanaerobacterium xylanolyticum LX-11
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 185826.81

構造登録者

Pengthaisong, S.,Ketudat Cairns, J.R. (登録日: 2023-05-09, 公開日: 2023-10-11)

主引用文献

Meelua, W.,Thinkumrob, N.,Saparpakorn, P.,Pengthaisong, S.,Hannongbua, S.,Ketudat Cairns, J.R.,Jitonnom, J.
Structural basis for inhibition of a GH116 beta-glucosidase and its missense mutants by GBA2 inhibitors: Crystallographic and quantum chemical study.
Chem.Biol.Interact., 384:110717-110717, 2023

PubMed Abstract: The crystal structure of the Thermoanaerobacterium xylanolyticum in glycoside hydrolase family 116 (TxGH116) β-glucosidase provides a structural model for human GBA2 glucosylceramidase, an enzyme defective in hereditary spastic paraplegia and a potential therapeutic target for treating Gaucher disease. To assess the therapeutic potential of known inhibitors, the X-ray structure of TxGH116 in complex with isofagomine (IFG) was determined at 2.0 Å resolution and showed the IFG bound in a relaxed chair conformation. The binding of IFG and 7 other iminosugar inhibitors to wild-type and mutant enzymes (Asp508His and Arg786His) mimicking GBA2 pathogenic variants was then evaluated computationally by two-layered ONIOM calculations (at the B3LYP:PM7 level). Calculations showed that six charged residues, Glu441, Asp452, His507, Asp593, Glu777, and Arg786 influence inhibitor binding most. His507, Glu777 and Arg786, form strong hydrogen bonds with the inhibitors (∼1.4-1.6 Å). Thus, the missense mutation of one of these residues in Arg786His has a greater effect on the interaction energies for all inhibitors compared to Asp508His. In line with the experimental data for the inhibitors that have been tested, the favorable interaction energy between the inhibitors and the TxGH116 protein followed the trend: isofagomine > 1-deoxynojirimycin > glucoimidazole > N-butyl-deoxynojirimycin ≈ N-nonyl-deoxynojirimycin > conduritol B epoxide ≈ azepane 1 > azepane 2. The obtained structural and energetic properties and comparison to the GBA2 model can lead to understanding of structural requirement for inhibitor binding in GH116 to aid the design of high potency GBA2 inhibitors.

PubMed: 37726065
DOI: 10.1016/j.cbi.2023.110717

実験手法

X-RAY DIFFRACTION (2 Å)