Sección de Biohelmintiasis, Instituto de Medicina Tropical, Facultad de Medicina, Universidad Central de Venezuela, Caracas, Venezuela.
Sección de Biohelmintiasis, Instituto de Medicina Tropical, Facultad de Medicina, Universidad Central de Venezuela, Caracas, Venezuela; Doctorado en Biotecnología, Pontificia Universidad Católica de Valparaiso - Universidad Técnica Federico Santa María.
Comput Biol Chem. 2019 Feb;78:18-27. doi: 10.1016/j.compbiolchem.2018.11.012. Epub 2018 Nov 19.
Asparaginyl endopeptidase (AE) of Schistosoma mansoni (Sm32), also known as legumain, is a cysteine protease indirectly involved in the digestion of hemoglobin of Schistosoma sp. in the gastrodermis, being a vaccine candidate against this trematode and a potential drug target. This study presents a model for the three-dimensional structure of Sm32 determined by means of homology modeling and a molecular dynamics simulation with explicit solvent refinement. The structure proved to be consistent with other AEs of known crystal structures described in their proenzyme form, revealing a catalytic domain that has a caspase-like overall structure and a C-terminal prodomain that adopts a death-domain-like architecture. We identified amino acid mutations in the βIV strand, differences in the active site and in the surface electrostatic potentials between Sm32 and its homologous proteins of mouse and human. Additionally, amino acid changes in the activation peptide (AP) of the S. mansoni protein were determined. Our results strongly suggest that Sm32 can be exploited as a potential target for drug design and for the development of biomarkers used in diagnosis and in novel vaccines for the control of parasitic infection, opening the perspective of medicinal chemistry developments.
曼氏血吸虫天冬氨酰内肽酶（AE）（Sm32），也称为组织蛋白酶 L，是一种半胱氨酸蛋白酶，间接参与曼氏血吸虫在胃皮层中血红蛋白的消化，是针对这种吸虫的候选疫苗，也是潜在的药物靶点。本研究通过同源建模和带显式溶剂精修的分子动力学模拟，提出了 Sm32 的三维结构模型。该结构与其他以酶原形式描述的已知晶体结构的 AE 一致，揭示了一个具有胱天蛋白酶样整体结构的催化结构域和一个采用死亡结构域样结构的 C 端前导结构域。我们鉴定了 Sm32 与同源的小鼠和人蛋白在 βIV 链上的氨基酸突变、活性位点的差异以及表面静电势的差异。此外，还确定了曼氏血吸虫蛋白的激活肽（AP）中的氨基酸变化。我们的研究结果强烈表明，Sm32 可以作为药物设计的潜在靶点，以及用于诊断和新型疫苗控制寄生虫感染的生物标志物，为药物化学的发展开辟了前景。
