Prediction of the mechanism of action of omuralide (clasto-lactacystin β-lactone) on human cathepsin A based on a structural model of the yeast proteasome β5/PRE2-subunit/omuralide complex
| Autor: | Fumiko Matsuzawa, Seiichi Aikawa, Yurie Satoh, Hirofumi Doi, Yoshito Kadota, Kohji Itoh |
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| Rok vydání: | 2006 |
| Předmět: |
Models
Molecular Proteasome Endopeptidase Complex Saccharomyces cerevisiae Proteins Macromolecular Substances Protein Conformation Stereochemistry Lactacystin Biophysics Cathepsin A Threonine protease Saccharomyces cerevisiae In Vitro Techniques Biochemistry Analytical Chemistry Serine Lactones chemistry.chemical_compound Catalytic Domain Humans Homology modeling Molecular Biology biology Carboxypeptidase Cysteine Endopeptidases Proteasome chemistry biology.protein Oxyanion hole |
| Zdroj: | Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics. 1764(8):1372-1380 |
| ISSN: | 1570-9639 |
| DOI: | 10.1016/j.bbapap.2006.05.008 |
| Popis: | Cathepsin A (CathA) is a lysosomal serine carboxypeptidase that exhibits homology and structural similarity to the yeast and wheat serine carboxypeptidases (CPY and CPW) belonging to the alpha/beta-hydrolase fold family. Human CathA (hCathA) and CPW have been demonstrated to be inhibited by a proteasome (threonine protease) inhibitor, lactacystin, and its active derivative, omuralide (clasto-lactacystin beta-lactone), as well as chymostatin. A hCathA/omuralide complex model constructed on the basis of the X-ray crystal structures of the CPW/chymostatin complex and the yeast proteasome beta-subunit (beta5/PRE2)/omuralide one predicted that the conformation of omuralide in the active-site cleft of proteasome beta5/PRE2 should be very similar to that of chymostatin at the S1 catalytic subsites in the hCathA- and CPW-complexes. The relative positions of the glycine residues, i.e., Gly57 in hCathA, Gly53 in CPW, and Gly47 in beta5/PRE2, present in the oxyanion hole of each enzyme were also highly conserved. These results suggest that omuralide might inhibit hCathA and CPW at the S1 subsite in their active-site clefts through direct binding to the active serine residue. |
| Databáze: | OpenAIRE |
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