化学
突变体
氢键
立体化学
生物化学
分子
有机化学
基因
作者
G. Kornhaber,Michael B. Tropak,Gustavo Maegawa,Steve Tuske,Stephen J. Coales,Don J. Mahuran,Yoshitomo Hamuro
出处
期刊:ChemBioChem
[Wiley]
日期:2008-10-28
卷期号:9 (16): 2643-2649
被引量:83
标识
DOI:10.1002/cbic.200800249
摘要
Abstract Structurally destabilizing mutations in acid β‐glucosidase (GCase) can result in Gaucher disease (GD). The iminosugar isofagomine (IFG), a competitive inhibitor and a potential pharmacological chaperone of GCase, is currently undergoing clinical evaluation for the treatment of GD. An X‐ray crystallographic study of the GCase‐IFG complex revealed a hydrogen bonding network between IFG and certain active site residues. It was suggested that this network may translate into greater global stability. Here it is demonstrated that IFG does increase the global stability of wild‐type GCase, shifting its melting curve by ∼15 °C and that it enhances mutant GCase activity in pre‐treated N370S/N370S and F213I/L444P patient fibroblasts. Additionally, amide hydrogen/deuterium exchange mass spectroscopy (H/D‐Ex) was employed to identify regions within GCase that undergo stabilization upon IFG‐binding. H/D‐Ex data indicate that the binding of IFG not only restricts the local protein dynamics of the active site, but also propagates this effect into surrounding regions.
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