title: Comparative analysis of binding energy of chymostatin with human cathepsin A and its homologous proteins by molecular orbital calculation.
abstract: Cathepsin A is a mammalian lysosomal enzyme that catalyzes the hydrolysis of the carboxy-terminal amino acids of polypeptides and also regulates beta-galactosidase and neuraminidase-1 activities through the formation of a multienzymic complex in lysosomes. Human cathepsin A (hCathA), yeast carboxypeptidase (CPY), and wheat carboxypeptidase II (CPW) belong to the alpha/beta-hydrolase fold family. They have structurally similar active-site clefts, but there are small differences in the amino acid residues comprising their active sites that might determine the substrate specificity and sensitivity to microbial inhibitors including chymostatin. To examine the selectivity and binding mechanism of chymostatin as to hCathA, CPY, and CPW at the atomic level, we analyzed the interaction energy between chymostatin and each protein quantitatively by semiempirical molecular orbital calculation AM1 with the continuum solvent model. We predicted the electrostatic repulsion between the P3 cyclic arginine residue of the inhibitor and the Arg344 in the S3 active subsite of hCathA. Genetic conversion of Arg344 of the wild-type hCathA to Ile also caused an increase in its sensitivity to chymostatin, which was correlated with the decrease in the interaction energy calculated with the molecular orbital method. The present results suggest that such molecular calculation should be useful for evaluating the interactions between ligands, including inhibitors and homologous enzymes, in their docking models.
authors.affiliation: Institute of Health Biosciences, The University of Tokushima Graduate School, 1-78 Shomachi, Tokushima 770-8505, Japan.
authors.forename: Tatsusada
authors.initials: T
authors.lastname: Yoshida
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Lepp
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Kadota
authors.forename: Yurie
authors.initials: Y
authors.lastname: Satoh
authors.forename: Kohji
authors.initials: K
authors.lastname: Itoh
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Chuman
mesh_terms: D001483:Base Sequence; D002268:Carboxypeptidases / Q000737:chemistry / Q000378:metabolism; D043402:Cathepsin A / Q000737:chemistry / Q000378:metabolism*; D018360:Crystallography, X-Ray; D017931:DNA Primers; D006801:Humans; D008958:Models, Molecular; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding
chemical_list: D017931:DNA Primers; D009842:Oligopeptides; C002101:chymostatin; D002268:Carboxypeptidases; D043402:Cathepsin A