Structural analysis of the catalytic site of AcCP-1, a cysteine proteinase secreted by the hookworm Ancylostoma caninum.
Previously, we have reported that hookworms secrete cysteine proteinase activity that is capable of cleaving the cathepsin L-specific substrate Z-Phe-Arg-AMC. We have also reported the gene sequences of novel cathepsin B-like proteinases from hookworms, but have been unable to locate cathepsin L-like genes that could account for the presence of the cathepsin L activity in these parasites. Here we present an homology model for the secreted hookworm cysteine proteinase AcCP-1 based upon the crystal structure co-ordinates of human cathepsin B. The model predicts that substrate binding and specificity differs between AcCP-1 and cathepsin B, and demonstrates that AcCP-1 would preferentially cleave Phe-Arg over Arg-Arg. This thereby provides an explanation for our previous observations that the hookworm proteinase, while structurally cathepsin B-like, displays a cathepsin L-like substrate specificity.
Brinkworth
R I
RI
Centre for Drug Design and Development, University of Queensland, St. Lucia, Australia.
Brindley
P J
PJ
Harrop
S A
SA
D000595:Amino Acid Sequence; D000722:Ancylostoma / Q000201:enzymology*; D000818:Animals; D001665:Binding Sites; D002403:Cathepsins / Q000737:chemistry / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000737:chemistry* / Q000378:metabolism; D016208:Databases, Factual; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D012984:Software; D013379:Substrate Specificity
D010455:Peptides; D002403:Cathepsins; D003546:Cysteine Endopeptidases