ArticleThe Journal of biological chemistry2010
Molecular basis of reduced glucosylceramidase activity in the most common Gaucher disease mutant, N370S.
Article in The Journal of biological chemistry, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 35 citations in OpenAlex.
- Targeting lysosomal pH restores mitochondrial quality control in GBA1-mutant Parkinson's disease.Translational neurodegeneration · 2026Article
- LRRK2 kinase mediates increased GCase activity in microglia in response to IFNγ-induced proinflammatory stimulation.NPJ Parkinson's disease · 2026Article
- Cost-effectiveness analysis of ambroxol for the treatment of Chinese patients with Gaucher disease.Frontiers in medicine · 2025Article
- A Type 3 Gaucher-Like Disease Due To Saposin C Deficiency in Two Emirati Families Caused by a Novel Splice Site Variant in the PSAP Gene.Journal of molecular neuroscience : MN · 2022Article
- Review
- Mechanism of glucocerebrosidase activation and dysfunction in Gaucher disease unraveled by molecular dynamics and deep learning.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- Computational modelling approaches as a potential platform to understand the molecular genetics association between Parkinson's and Gaucher diseases.Metabolic brain disease · 2018Article
- Distinguishing the differences in β-glycosylceramidase folds, dynamics, and actions informs therapeutic uses.Journal of lipid research · 2018Article
- Mitochondrial dysfunction associated with glucocerebrosidase deficiency.Neurobiology of disease · 2016Review
- Glycosylation is crucial for a proper catalytic site organization in human glucocerebrosidase.Glycoconjugate journal · 2016Article
- Article
- Extrapolating the effect of deleterious nsSNPs in the binding adaptability of flavopiridol with CDK7 protein: a molecular dynamics approach.Human genomics · 2013Article
- A bicyclic 1-deoxygalactonojirimycin derivative as a novel pharmacological chaperone for GM1 gangliosidosis.Molecular therapy : the journal of the American Society of Gene Therapy · 2013Article
- The role of saposin C in Gaucher disease.Molecular genetics and metabolism · 2012Review
- Histone deacetylase inhibitors prevent the degradation and restore the activity of glucocerebrosidase in Gaucher disease.Proceedings of the National Academy of Sciences of the United States of America · 2011Article
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Authors and funding
5 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Gaucher disease is caused by the defective activity of the lysosomal hydrolase, glucosylceramidase. Although the x-ray structure of wild type glucosylceramidase has been resolved, little is known about the structural features of any of the >200 mutations. Various treatments for Gaucher disease are available, including enzyme replacement and chaperone therapies. The latter involves binding of competitive inhibitors at the active site to enable correct folding and transport of the mutant enzyme to the lysosome. We now use molecular dynamics, a set of structural analysis tools, and several statistical methods to determine the flexible behavior of the N370S Gaucher mutant at various pH values, with and without binding the chaperone, N-butyl-deoxynojirimycin. We focus on the effect of the chaperone on the whole protein, on the active site, and on three important structural loops, and we demonstrate how the chaperone modifies the behavior of N370S in such a way that it becomes more active at lysosomal pH. Our results suggest a mechanism whereby the binding of N-butyl-deoxynojirimycin helps target correctly folded glucosylceramidase to the lysosome, contributes to binding with saposin C, and explains the initiation of the substrate-enzyme complex. Such analysis provides a new framework for determination of the structure of other Gaucher disease mutants and suggests new approaches for rational drug design.
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