Title : Structural basis of pharmacological chaperoning for human β
-galactosidase
Abstract :
- GM1 gangliosidosis and Morquio B disease are autosomal recessive diseases caused by the defect in the lysosomal β -galactosidase (β-Gal), frequently related to misfolding and subsequent endoplasmic reticulum-associated degradation
- Pharmacological chaperone (PC) therapy is a newly developed molecular therapeutic approach by using small molecule ligands of the mutant enzyme that are able to promote the correct folding and prevent endoplasmic reticulum-associated degradation and promote trafficking to the lysosome
- In this report, we describe the enzymological properties of purified recombinant human β-Gal(WT) and two representative mutations in GM1 gangliosidosis Japanese patients, β-Gal(R201C) and β-Gal(I51T)
- We have also evaluated the PC effect of two competitive inhibitors of β-Gal
- Moreover, we provide a detailed atomic view of the recognition mechanism of these compounds in comparison with two structurally related analogues
- All compounds bind to the active site of β-Gal with the sugar-mimicking moiety making hydrogen bonds to active site residues
- Moreover, the binding affinity, the enzyme selectivity, and the PC potential are strongly affected by the mono- or bicyclic structure of the core as well as the orientation, nature, and length of the exocyclic substituent
- These results provide understanding on the mechanism of action of β-Gal selective chaperoning by newly developed PC compounds
Output (sent_index, trigger,
protein,
sugar,
site):
Output(Part-Of) (sent_index,
protein,
site):
*Output_Site_Fusion* (sent_index,
protein,
sugar,
site):