4cia

From Proteopedia

(Difference between revisions)

Current revision

Crystal structure of cathepsin A, complexed with compound 1

Structural highlights

4cia is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.98Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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 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^[6]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Zhou XY, Galjart NJ, Willemsen R, Gillemans N, Galjaard H, d'Azzo A. A mutation in a mild form of galactosialidosis impairs dimerization of the protective protein and renders it unstable. EMBO J. 1991 Dec;10(13):4041-8. PMID:1756715
↑ Shimmoto M, Fukuhara Y, Itoh K, Oshima A, Sakuraba H, Suzuki Y. Protective protein gene mutations in galactosialidosis. J Clin Invest. 1993 Jun;91(6):2393-8. PMID:8514852 doi:http://dx.doi.org/10.1172/JCI116472
↑ Zhou XY, van der Spoel A, Rottier R, Hale G, Willemsen R, Berry GT, Strisciuglio P, Morrone A, Zammarchi E, Andria G, d'Azzo A. Molecular and biochemical analysis of protective protein/cathepsin A mutations: correlation with clinical severity in galactosialidosis. Hum Mol Genet. 1996 Dec;5(12):1977-87. PMID:8968752
↑ Takiguchi K, Itoh K, Shimmoto M, Ozand PT, Doi H, Sakuraba H. Structural and functional study of K453E mutant protective protein/cathepsin A causing the late infantile form of galactosialidosis. J Hum Genet. 2000;45(4):200-6. PMID:10944848 doi:10.1007/s100380070027
↑ Galjart NJ, Morreau H, Willemsen R, Gillemans N, Bonten EJ, d'Azzo A. Human lysosomal protective protein has cathepsin A-like activity distinct from its protective function. J Biol Chem. 1991 Aug 5;266(22):14754-62. PMID:1907282
↑ Schreuder HA, Liesum A, Kroll K, Bohnisch B, Buning C, Ruf S, Sadowski T. Crystal structure of cathepsin A, a novel target for the treatment of cardiovascular diseases. Biochem Biophys Res Commun. 2014 Feb 12. pii: S0006-291X(14)00266-6. doi:, 10.1016/j.bbrc.2014.02.014. PMID:24530914 doi:http://dx.doi.org/10.1016/j.bbrc.2014.02.014

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4cia"

@@ Line 4: / Line 4: @@
 == 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='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>
+</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>
+[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>
+[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 ==

4cia

From Proteopedia

Current revision

Crystal structure of cathepsin A, complexed with compound 1

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

Personal tools

Navigation

Search

Toolbox