4NXS
Crystal structure of human alpha-galactosidase A in complex with 1-deoxygalactonojirimycin-pFPhT
Summary for 4NXS
| Entry DOI | 10.2210/pdb4nxs/pdb |
| Descriptor | Alpha-galactosidase A, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, SULFATE ION, ... (6 entities in total) |
| Functional Keywords | pharmacological chaperone, drug delivery systems, enzyme activation, enzyme stability, humans, lysosomes, molecular chaperones, protein binding, alpha-galactosidase, hydrolase-hydrolase inhibitor complex, fabry disease, gla gene, arylthiourea, hydrolase/hydrolase inhibitor |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 2 |
| Total formula weight | 93635.73 |
| Authors | Johnson, J.L.,Drury, J.E.,Lieberman, R.L. (deposition date: 2013-12-09, release date: 2014-06-11, Last modification date: 2024-10-30) |
| Primary citation | Yu, Y.,Mena-Barragan, T.,Higaki, K.,Johnson, J.L.,Drury, J.E.,Lieberman, R.L.,Nakasone, N.,Ninomiya, H.,Tsukimura, T.,Sakuraba, H.,Suzuki, Y.,Nanba, E.,Mellet, C.O.,Garcia Fernandez, J.M.,Ohno, K. Molecular Basis of 1-Deoxygalactonojirimycin Arylthiourea Binding to Human alpha-Galactosidase A: Pharmacological Chaperoning Efficacy on Fabry Disease Mutants. Acs Chem.Biol., 9:1460-1469, 2014 Cited by PubMed Abstract: Fabry disease (FD) is an X-linked lysosomal storage disorder caused by mutations in the GLA gene often leading to missense α-galactosidase A (α-Gal A) variants that undergo premature endoplasmic reticulum-associated degradation due to folding defects. We have synthesized and characterized a new family of neutral amphiphilic pharmacological chaperones, namely 1-deoxygalactonojirimycin-arylthioureas (DGJ-ArTs), capable of stabilizing α-Gal A and restoring trafficking. Binding to the enzyme is reinforced by a strong hydrogen bond involving the aryl-N'H thiourea proton and the catalytic aspartic acid acid D231 of α-Gal A, as confirmed by a 2.55 Å resolution cocrystal structure. Selected candidates enhanced α-Gal A activity and ameliorate globotriaosylceramide (Gb3) accumulation and autophagy impairments in FD cell cultures. Moreover, they acted synergistically with the proteostasis regulator 4-phenylbutyric acid, appearing to be promising leads as pharmacological chaperones for FD. PubMed: 24783948DOI: 10.1021/cb500143h PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.5493 Å) |
Structure validation
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