4az0: Difference between revisions
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<StructureSection load='4az0' size='340' side='right'caption='[[4az0]], [[Resolution|resolution]] 2.17Å' scene=''> | <StructureSection load='4az0' size='340' side='right'caption='[[4az0]], [[Resolution|resolution]] 2.17Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4az0]] is a 2 chain structure | <table><tr><td colspan='2'>[[4az0]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4AZ0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4AZ0 FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CD:CADMIUM+ION'>CD | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CD:CADMIUM+ION'>CD</scene>, <scene name='pdbligand=S61:(S)-3-{[1-(2-FLUORO-PHENYL)-5-HYDROXY-1H-PYRAZOLE-3-CARBONYL]-AMINO}-3-O-TOLYL-PROPIONIC+ACID'>S61</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr> | ||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1ivy|1ivy]], [[4az3|4az3]]</td></tr> | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[1ivy|1ivy]], [[4az3|4az3]]</div></td></tr> | ||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[ | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Carboxypeptidase_C Carboxypeptidase C], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.16.5 3.4.16.5] </span></td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4az0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4az0 OCA], [https://pdbe.org/4az0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4az0 RCSB], [https://www.ebi.ac.uk/pdbsum/4az0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4az0 ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Disease == | == 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 == | == 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;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
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</StructureSection> | </StructureSection> | ||
[[Category: Carboxypeptidase C]] | [[Category: Carboxypeptidase C]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Buning, C]] | [[Category: Buning, C]] | ||
Revision as of 08:51, 25 August 2022
crystal structure of cathepsin a, complexed with 8a.crystal structure of cathepsin a, complexed with 8a.
Structural highlights
Disease[PPGB_HUMAN] Defects in CTSA are the cause of galactosialidosis (GSL) [MIM: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.[1] [2] [3] [4] Function[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.[5] Publication Abstract from PubMedCathepsin A (CatA) is a serine carboxypeptidase distributed between lysosomes, cell membrane, and extracellular space. Several peptide hormones including bradykinin and angiotensin I have been described as substrates. Therefore, the inhibition of CatA has the potential for beneficial effects in cardiovascular diseases. Pharmacological inhibition of CatA by the natural product ebelactone B increased renal bradykinin levels and prevented the development of salt-induced hypertension. However, so far no small molecule inhibitors of CatA with oral bioavailability have been described to allow further pharmacological profiling. In our work we identified novel beta-amino acid derivatives as inhibitors of CatA after a HTS analysis based on a project adapted fragment approach. The new inhibitors showed beneficial ADME and pharmacokinetic profiles, and their binding modes were established by X-ray crystallography. Further investigations led to the identification of a hitherto unknown pathophysiological role of CatA in cardiac hypertrophy. One of our inhibitors is currently undergoing phase I clinical trials. Novel beta-Amino Acid Derivatives as Inhibitors of Cathepsin A.,Ruf S, Buning C, Schreuder H, Horstick G, Linz W, Olpp T, Pernerstorfer J, Hiss K, Kroll K, Kannt A, Kohlmann M, Linz D, Hubschle T, Rutten H, Wirth K, Schmidt T, Sadowski T J Med Chem. 2012 Sep 13;55(17):7636-49. Epub 2012 Aug 16. PMID:22861813[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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