4az0

crystal structure of cathepsin a, complexed with 8a.

spinqualitylabelsall models 4az0, resolution 2.17Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4az0 is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: CD, NAG, S61 Related: 1ivy, 4az3 Activity: Carboxypeptidase C, with EC number 3.4.16.5 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. 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. Publication Abstract from PubMed Cathepsin 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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