Abstract
Protein folding in cells occurs in the presence of high concentrations of endogenous binding partners, and exogenous binding partners have been exploited as pharmacological chaperones. A combined mathematical modeling and experimental approach shows that a ligand improves the folding of a destabilized protein by biasing the kinetic partitioning between folding and alternative fates (aggregation or degradation). Computationally predicted inhibition of test protein aggregation and degradation as a function of ligand concentration are validated by experiments in two disparate cellular systems.
MeSH terms
-
1-Deoxynojirimycin / analogs & derivatives
-
1-Deoxynojirimycin / metabolism
-
1-Deoxynojirimycin / pharmacology
-
Escherichia coli / chemistry
-
Escherichia coli / genetics
-
Escherichia coli / metabolism
-
HEK293 Cells
-
Humans
-
Kinetics
-
Ligands*
-
Models, Molecular
-
Molecular Chaperones / pharmacology*
-
Protein Aggregates / drug effects*
-
Protein Folding / drug effects*
-
Proteolysis / drug effects*
-
Reproducibility of Results
-
Tetrahydrofolate Dehydrogenase / chemistry
-
Tetrahydrofolate Dehydrogenase / metabolism
-
Trimethoprim / metabolism
-
Trimethoprim / pharmacology
-
alpha-Galactosidase / chemistry
-
alpha-Galactosidase / metabolism
Substances
-
Ligands
-
Molecular Chaperones
-
Protein Aggregates
-
1-Deoxynojirimycin
-
Trimethoprim
-
migalastat
-
Tetrahydrofolate Dehydrogenase
-
GLA protein, human
-
alpha-Galactosidase