Exploring the subsite specificity of Schistosoma mansoni aspartyl hemoglobinase through comparative molecular modelling

FEBS Letters

Katz, N.¹  Giovanni-De-Simone, S.²  Ribeiro, F.¹  Silva, F.P.² 

[1] Centro de Pesquisas René Rachou, FIOCRUZ, Belo Horizonte-MG, Brazil;Laboratório de Bioquı́mica de Proteı́nas e Peptı́deos, Departamento de Bioquı́mica e Biologia Molecular, Instituto Oswaldo Cruz, FIOCRUZ, Rio de Janeiro-RJ, Brazil

关键词: Schistosomiasis;    Aspartyl hemoglobinase;    Specificity;    Cathepsin D;    Schistosoma mansoni;    3D;    three dimensional;   

DOI  :  10.1016/S0014-5793(02)02270-6

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

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.

【 授权许可】

Unknown