title: Exploring the subsite specificity of Schistosoma mansoni aspartyl hemoglobinase through comparative molecular modelling.
abstract: Blood flukes of the genus Schistosoma currently infect millions of people in tropical and subtropical countries. An enzyme playing a major role in hemoglobin (Hb) degradation by Schistosoma mansoni has been cloned and shown to be highly similar to the human cathepsin D aspartyl proteinase, although presenting a distinct substrate specificity from the latter. Investigating the structural features responsible for this difference has a major application in the design of selective anti-schistosomal drugs. In order to achieve this goal a homology model for the S. mansoni aspartyl hemoglobinase was constructed and then used to simulate the complexes formed with two transition state analogues of Hb-derived octapeptide substrates. Comparison with human cathepsin D showed that different pocket volumes and surface electrostatic potentials arise from substitutions in residues comprising the S4, S3, S2 and S3' subsites. Since the primary specificity of the S. mansoni enzyme resembles that of HIV-1 protease, we have discussed the applicability of current retroviral protease inhibitors as leads for the design of new anti-schistosomal drugs.
authors.affiliation: Laboratório de Bioquímica de Proteínas e Peptídeos, Departamento de Bioquímica e Biologia Molecular, Instituto Oswaldo Cruz, FIOCRUZ, Rio de Janeiro-RJ, Brazil
authors.forename: F P
authors.initials: FP
authors.lastname: Silva
authors.forename: F
authors.initials: F
authors.lastname: Ribeiro
authors.forename: N
authors.initials: N
authors.lastname: Katz
authors.forename: S
authors.initials: S
authors.lastname: Giovanni-De-Simone
mesh_terms: D000818:Animals; D001665:Binding Sites; D002402:Cathepsin D / Q000737:chemistry / Q000502:physiology; D003546:Cysteine Endopeptidases / Q000737:chemistry* / Q000502:physiology*; D016333:HIV Protease / Q000737:chemistry; D015801:Helminth Proteins; D006454:Hemoglobins / Q000737:chemistry; D006801:Humans; D046911:Macromolecular Substances; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry; D010802:Phylogeny; D012550:Schistosoma mansoni / Q000201:enzymology*; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship; D013379:Substrate Specificity / Q000502:physiology
chemical_list: D015801:Helminth Proteins; D006454:Hemoglobins; D046911:Macromolecular Substances; D010446:Peptide Fragments; D003546:Cysteine Endopeptidases; D016333:HIV Protease; D002402:Cathepsin D