4mxu: Difference between revisions
New page: '''Unreleased structure''' The entry 4mxu is ON HOLD Authors: Wijayasinghe, Y.S., Pavlovsky, A.G., Viola, R.E. Description: Human brain aspartoacylase mutant K213E complex with interme... |
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The | ==Human brain aspartoacylase mutant K213E complex with intermediate analog (N-phosphonomethyl-L-aspartate)== | ||
<StructureSection load='4mxu' size='340' side='right'caption='[[4mxu]], [[Resolution|resolution]] 2.60Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4mxu]] 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=4MXU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4MXU 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]] 2.6Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=AS9:N-[HYDROXY(METHYL)PHOSPHORYL]-L-ASPARTIC+ACID'>AS9</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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=4mxu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4mxu OCA], [https://pdbe.org/4mxu PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4mxu RCSB], [https://www.ebi.ac.uk/pdbsum/4mxu PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4mxu ProSAT]</span></td></tr> | |||
</table> | |||
== Disease == | |||
[https://www.uniprot.org/uniprot/ACY2_HUMAN ACY2_HUMAN] Defects in ASPA are the cause of Canavan disease (CAND) [MIM:[https://omim.org/entry/271900 271900]; also known as spongy degeneration of the brain. CAND is a rare neurodegenerative condition of infancy or childhood characterized by white matter vacuolization and demeylination that gives rise to a spongy appearance. The clinical features are onset in early infancy, atonia of neck muscles, hypotonia, hyperextension of legs and flexion of arms, blindness, severe mental defect, megalocephaly, and death by 18 months on the average.<ref>PMID:8252036</ref> <ref>PMID:12706335</ref> <ref>PMID:8023850</ref> <ref>PMID:7668285</ref> <ref>PMID:7599639</ref> <ref>PMID:8659549</ref> <ref>PMID:9452117</ref> <ref>PMID:10564886</ref> <ref>PMID:10407784</ref> <ref>PMID:10909858</ref> <ref>PMID:12638939</ref> <ref>PMID:12205125</ref> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/ACY2_HUMAN ACY2_HUMAN] Catalyzes the deacetylation of N-acetylaspartic acid (NAA) to produce acetate and L-aspartate. NAA occurs in high concentration in brain and its hydrolysis NAA plays a significant part in the maintenance of intact white matter. In other tissues it act as a scavenger of NAA from body fluids. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Canavan disease (CD) is a fatal, childhood neurological disorder caused by mutations in the ASPA gene, leading to catalytic deficiencies in the aspartoacylase (ASPA) enzyme and impaired N-acetyl-l-aspartic acid metabolism in the brain. To study the possible structural defects triggered by these mutations, four ASPA missense mutations associated with different disease severities have been structurally characterized. These mutant enzymes each have overall structures similar to that of the native ASPA enzyme, but with varying degrees of alterations that offer explanations for the respective loss of catalytic activity. The K213E mutant, a nonconservative mutant associated with a mild disease phenotype, has minimal structural differences compared to the native enzyme. In contrast, the loss of van der Waals contacts in the F295S mutant and the loss of hydrophobic and hydrogen bonding interactions in the Y231C mutant lead to a local collapse of the hydrophobic core structure in the carboxyl-terminal domain, contributing to a decrease in protein stability. The structure of the E285A mutant, the most common clinical mutant, reveals that the loss of hydrogen bonding interactions with the carboxylate side chain of Glu285 disturbs the active site architecture, leading to altered substrate binding and lower catalytic activity. Our improved understanding of the nature of these structural defects provides a basis for the development of treatment therapies for CD. | |||
Aspartoacylase Catalytic Deficiency as the Cause of Canavan Disease: A Structural Perspective.,Wijayasinghe YS, Pavlovsky AG, Viola RE Biochemistry. 2014 Jul 16. PMID:25003821<ref>PMID:25003821</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 4mxu" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Aminoacylase 3D structures|Aminoacylase 3D structures]] | |||
*[[Aspartoacylase 3D structures|Aspartoacylase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Pavlovsky AG]] | |||
[[Category: Viola RE]] | |||
[[Category: Wijayasinghe YS]] | |||