8JBO
Crystal structure of TxGH116 from Thermoanaerobacterium xylanolyticum with isofagomine
Summary for 8JBO
| Entry DOI | 10.2210/pdb8jbo/pdb |
| Related | 5BVU 5BX2 5BX3 5BX4 5BX5 |
| Descriptor | Glucosylceramidase, 5-HYDROXYMETHYL-3,4-DIHYDROXYPIPERIDINE, CALCIUM ION, ... (6 entities in total) |
| Functional Keywords | txgh116, beta-glucosidase, acid/base mutant, thermoanaerobacterium xylanolyticum, cellobiose, hydrolase |
| Biological source | Thermoanaerobacterium xylanolyticum LX-11 |
| Total number of polymer chains | 2 |
| Total formula weight | 185826.81 |
| Authors | |
| Primary citation | 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 Cited by 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: 37726065DOI: 10.1016/j.cbi.2023.110717 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2 Å) |
Structure validation
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