View source for 4nxs


==Crystal structure of human alpha-galactosidase A in complex with 1-deoxygalactonojirimycin-pFPhT==
<StructureSection load='4nxs' size='340' side='right'caption='[[4nxs]], [[Resolution|resolution]] 2.55&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4nxs]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4NXS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4NXS FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.5493&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2OZ:(2R,3S,4R,5S)-N-(4-FLUOROPHENYL)-3,4,5-TRIHYDROXY-2-(HYDROXYMETHYL)PIPERIDINE-1-CARBOTHIOAMIDE'>2OZ</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4nxs FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4nxs OCA], [https://pdbe.org/4nxs PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4nxs RCSB], [https://www.ebi.ac.uk/pdbsum/4nxs PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4nxs ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/AGAL_HUMAN AGAL_HUMAN] Defects in GLA are the cause of Fabry disease (FD) [MIM:[https://omim.org/entry/301500 301500]. FD is a rare X-linked sphingolipidosis disease where glycolipid accumulates in many tissues. The disease consists of an inborn error of glycosphingolipid catabolism. FD patients show systemic accumulation of globotriaoslyceramide (Gb3) and related glycosphingolipids in the plasma and cellular lysosomes throughout the body. Clinical recognition in males results from characteristic skin lesions (angiokeratomas) over the lower trunk. Patients may show ocular deposits, febrile episodes, and burning pain in the extremities. Death results from renal failure, cardiac or cerebral complications of hypertension or other vascular disease. Heterozygous females may exhibit the disorder in an attenuated form, they are more likely to show corneal opacities.<ref>PMID:2152885</ref> <ref>PMID:1846223</ref> <ref>PMID:2171331</ref> <ref>PMID:2539398</ref> <ref>PMID:1315715</ref> <ref>PMID:7504405</ref> <ref>PMID:8395937</ref> <ref>PMID:8069316</ref> <ref>PMID:7531540</ref> <ref>PMID:7575533</ref> <ref>PMID:7759078</ref> <ref>PMID:7599642</ref> <ref>PMID:7596372</ref> <ref>PMID:8738659</ref> <ref>PMID:8875188</ref> <ref>PMID:8834244</ref> <ref>PMID:8931708</ref> <ref>PMID:8807334</ref> <ref>PMID:8863162</ref> <ref>PMID:9105656</ref> <ref>PMID:9100224</ref> <ref>PMID:9554750</ref> <ref>PMID:9452068</ref> <ref>PMID:9452090</ref> <ref>PMID:9452111</ref> <ref>PMID:10208848</ref> <ref>PMID:10090526</ref> <ref>PMID:10838196</ref> <ref>PMID:10666480</ref> <ref>PMID:11076046</ref> <ref>PMID:10916280</ref> <ref>PMID:11295840</ref> <ref>PMID:11668641</ref> <ref>PMID:11889412</ref> <ref>PMID:12694230</ref> <ref>PMID:12786754</ref> <ref>PMID:15162124</ref> <ref>PMID:15712228</ref> <ref>PMID:16533976</ref> <ref>PMID:19621417</ref> 
== Function ==
[https://www.uniprot.org/uniprot/AGAL_HUMAN AGAL_HUMAN] 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Fabry disease (FD) is an X-linked lysosomal storage disorder caused by mutations in the GLA gene often leading to missense alpha-galactosidase A (alpha-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 alpha-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 alpha-Gal A, as confirmed by a 2.55 A resolution cocrystal structure. Selected candidates enhanced alpha-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.

Molecular Basis of 1-Deoxygalactonojirimycin Arylthiourea Binding to Human alpha-Galactosidase A: Pharmacological Chaperoning Efficacy on Fabry Disease Mutants.,Yu Y, Mena-Barragan T, Higaki K, Johnson JL, Drury JE, Lieberman RL, Nakasone N, Ninomiya H, Tsukimura T, Sakuraba H, Suzuki Y, Nanba E, Mellet CO, Garcia Fernandez JM, Ohno K ACS Chem Biol. 2014 May 12. PMID:24783948<ref>PMID:24783948</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4nxs" style="background-color:#fffaf0;"></div>

==See Also==
*[[Galactosidase 3D structures|Galactosidase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Drury JE]]
[[Category: Johnson JL]]
[[Category: Lieberman RL]]