View source for 4cia


==Crystal structure of cathepsin A, complexed with compound 1==
<StructureSection load='4cia' size='340' side='right'caption='[[4cia]], [[Resolution|resolution]] 1.98&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4cia]] is a 1 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=4CIA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4CIA 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]] 1.98&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6KZ:N-[(2S)-4-METHYL-1-OXIDANYLIDENE-1-[[(1R,2S)-1-OXIDANYL-1-(5-PHENYL-1,2,4-OXADIAZOL-3-YL)BUTAN-2-YL]AMINO]PENTAN-2-YL]MORPHOLINE-4-CARBOXAMIDE'>6KZ</scene>, <scene name='pdbligand=CD:CADMIUM+ION'>CD</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</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=4cia FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4cia OCA], [https://pdbe.org/4cia PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4cia RCSB], [https://www.ebi.ac.uk/pdbsum/4cia PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4cia ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/PPGB_HUMAN PPGB_HUMAN] Defects in CTSA are the cause of galactosialidosis (GSL) [MIM:[https://omim.org/entry/256540 256540]. A lysosomal storage disease associated with a combined deficiency of beta-galactosidase and neuraminidase, secondary to a defect in cathepsin A. All patients have clinical manifestations typical of a lysosomal disorder, such as coarse facies, cherry red spots, vertebral changes, foam cells in the bone marrow, and vacuolated lymphocytes. Three phenotypic subtypes are recognized. The early infantile form is associated with fetal hydrops, edema, ascites, visceromegaly, skeletal dysplasia, and early death. The late infantile type is characterized by hepatosplenomegaly, growth retardation, cardiac involvement, and a normal or mildly affected mental state. The juvenile/adult form is characterized by myoclonus, ataxia, angiokeratoma, mental retardation, neurologic deterioration, absence of visceromegaly, and long survival.<ref>PMID:1756715</ref> <ref>PMID:8514852</ref> <ref>PMID:8968752</ref> <ref>PMID:10944848</ref> 
== Function ==
[https://www.uniprot.org/uniprot/PPGB_HUMAN PPGB_HUMAN] Protective protein appears to be essential for both the activity of beta-galactosidase and neuraminidase, it associates with these enzymes and exerts a protective function necessary for their stability and activity. This protein is also a carboxypeptidase and can deamidate tachykinins.<ref>PMID:1907282</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The lysosomal serine carboxypeptidase cathepsin A is involved in the breakdown of peptide hormones like endothelin and bradykinin. Recent pharmacological studies with cathepsin A inhibitors in rodents showed a remarkable reduction in cardiac hypertrophy and atrial fibrillation, making cathepsin A a promising target for the treatment of heart failure. Here we describe the crystal structures of activated cathepsin A without inhibitor and with two compounds that mimic the tetrahedral intermediate and the reaction product, respectively. The structure of activated cathepsin A turned out to be very similar to the structure of the inactive precursor. The only difference was the removal of a 40 residue activation domain, partially due to proteolytic removal of the activation peptide, and partially by an order-disorder transition of the peptides flanking the removed activation peptide. The termini of the catalytic core are held together by the Cys253-Cys303 disulfide bond, just before and after the activation domain. One of the compounds we soaked in our crystals reacted covalently with the catalytic Ser150 and formed a tetrahedral intermediate. The other compound got cleaved by the enzyme and a fragment, resembling one of the natural reaction products, was found in the active site. These studies establish cathepsin A as a classical serine proteinase with a well-defined oxyanion hole. The carboxylate group of the cleavage product is bound by a hydrogen-bonding network involving one aspartate and two glutamate side chains. This network can only form if at least half of the carboxylate groups involved are protonated, which explains the acidic pH optimum of the enzyme.

Crystal structure of cathepsin A, a novel target for the treatment of cardiovascular diseases.,Schreuder HA, Liesum A, Kroll K, Bohnisch B, Buning C, Ruf S, Sadowski T Biochem Biophys Res Commun. 2014 Feb 12. pii: S0006-291X(14)00266-6. doi:, 10.1016/j.bbrc.2014.02.014. PMID:24530914<ref>PMID:24530914</ref>

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

==See Also==
*[[Cathepsin 3D structures|Cathepsin 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Boehnisch B]]
[[Category: Buning C]]
[[Category: Kroll K]]
[[Category: Liesum A]]
[[Category: Ruf S]]
[[Category: Sadowski T]]
[[Category: Schreuder HA]]