Identification of an Allosteric Binding Site on Human Lysosomal Alpha-Galactosidase Opens the Way to New Pharmacological Chaperones for Fabry Disease

Personalized therapies are required for Fabry disease due to its large phenotypic spectrum and numerous different genotypes. In principle, missense mutations that do not affect the active site could be rescued with pharmacological chaperones. At present pharmacological chaperones for Fabry disease b...

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Published in:PloS one 2016-10, Vol.11 (10), p.e0165463-e0165463
Main Authors: Citro, Valentina, Peña-García, Jorge, den-Haan, Helena, Pérez-Sánchez, Horacio, Del Prete, Rosita, Liguori, Ludovica, Cimmaruta, Chiara, Lukas, Jan, Cubellis, Maria Vittoria, Andreotti, Giuseppina
Format: Article
Language:English
Subjects:
a-Galactosidase
Allosteric properties
Allosteric Site - drug effects
alpha-Galactosidase - chemistry
alpha-Galactosidase - genetics
alpha-Galactosidase - metabolism
Animals
Binding sites
Bioinformatics
Biology and Life Sciences
Catalytic Domain
Chaperones
Chlorocebus aethiops
Computer engineering
COS Cells
Disease
Docking
Drug dosages
Enzymes
Fabry Disease - drug therapy
Fabry Disease - enzymology
Fabry Disease - genetics
Fabry's disease
Galactose
Galactosidase
Genetic aspects
Genotypes
Humans
Ligands
Lysosomes - enzymology
Medical screening
Medicine and Health Sciences
Methods
Missense mutation
Molecular Docking Simulation
Mutation
Pharmacology
Physical Sciences
Proteins
Purines - metabolism
Purines - pharmacology
Purines - therapeutic use
Research and Analysis Methods
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cited_by cdi_FETCH-LOGICAL-c791t-90fb5a9132c437612de884f498d7e86d1249cf9fc7c1680136b71c3a774342013
cites cdi_FETCH-LOGICAL-c791t-90fb5a9132c437612de884f498d7e86d1249cf9fc7c1680136b71c3a774342013
container_end_page e0165463
container_issue 10
container_start_page e0165463
container_title PloS one
container_volume 11
creator Citro, Valentina
Peña-García, Jorge
den-Haan, Helena
Pérez-Sánchez, Horacio
Del Prete, Rosita
Liguori, Ludovica
Cimmaruta, Chiara
Lukas, Jan
Cubellis, Maria Vittoria
Andreotti, Giuseppina
description Personalized therapies are required for Fabry disease due to its large phenotypic spectrum and numerous different genotypes. In principle, missense mutations that do not affect the active site could be rescued with pharmacological chaperones. At present pharmacological chaperones for Fabry disease bind the active site and couple a stabilizing effect, which is required, to an inhibitory effect, which is deleterious. By in silico docking we identified an allosteric hot-spot for ligand binding where a drug-like compound, 2,6-dithiopurine, binds preferentially. 2,6-dithiopurine stabilizes lysosomal alpha-galactosidase in vitro and rescues a mutant that is not responsive to a mono-therapy with previously described pharmacological chaperones, 1-deoxygalactonojirimycin and galactose in a cell based assay.
doi_str_mv 10.1371/journal.pone.0165463
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1932-6203
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subjects a-Galactosidase
Allosteric properties
Allosteric Site - drug effects
alpha-Galactosidase - chemistry
alpha-Galactosidase - genetics
alpha-Galactosidase - metabolism
Animals
Binding sites
Bioinformatics
Biology and Life Sciences
Catalytic Domain
Chaperones
Chlorocebus aethiops
Computer engineering
COS Cells
Disease
Docking
Drug dosages
Enzymes
Fabry Disease - drug therapy
Fabry Disease - enzymology
Fabry Disease - genetics
Fabry's disease
Galactose
Galactosidase
Genetic aspects
Genotypes
Humans
Ligands
Lysosomes - enzymology
Medical screening
Medicine and Health Sciences
Methods
Missense mutation
Molecular Docking Simulation
Mutation
Pharmacology
Physical Sciences
Proteins
Purines - metabolism
Purines - pharmacology
Purines - therapeutic use
Research and Analysis Methods
title Identification of an Allosteric Binding Site on Human Lysosomal Alpha-Galactosidase Opens the Way to New Pharmacological Chaperones for Fabry Disease
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