Structural analysis of secretory phospholipase A2 from Clonorchis sinensis: therapeutic implications for hepatic fibrosis
Hepatic fibrosis is a common complication of the infection by the parasite, Clonorchis sinensis. There is a high incidence of this disease in the Asian countries with an increased risk of conversion to cancer. A secretory phospholipase A2 (PLA2) enzyme from the parasite is implicated in the pathology. This is an attractive drug target in the light of extensive structural characterization of this class of enzyme. In this study, the structure of the enzyme was modeled based on its sequence homology to the group III bee venom PLA2. On analysis, the overall structure essentially is comprised of three helices, two sets of β-wings and an elongated C-terminal extension. The structure is stabilized by four disulfide bonds. The structure is comprised of a calcium binding loop, active site and a substrate binding hydrophobic channel. The active site of the enzyme shows the classical features of PLA2 with the participation of the three residues: histidine-aspartic acid-tyrosine in hydrogen bond formation. This is an interesting variation from the house keeping group III PLA2 enzyme of human which has a histidine-aspartic acid and phenylalanine arrangement at the active site. This difference is therefore an important structural parameter that can be exploited to design specific inhibitor molecules against the pathogen PLA2. Likewise, there are certain unique structural features in the hydrophobic channel and the putative membrane binding surface of the PLA2 from Clonorchis sinensis that not only help understand the mechanism of action but also provide knowledge for a targeted therapy of liver fibrosis caused by the parasite.
KeywordsClonorchis sinensis Drug target Group III phospholipase A2 Hepatic fibrosis
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GH acknowledges the project grant (SR/FT/18) from Department of Science and Technology, Government of India and the ‘Pool Officer’ fellowship from the Council of Scientific and Industrial Research, Government of India. The financial support to the Biomedical Informatics Center at the institute by Indian Council of Medical Research, Government of India, is gratefully acknowledged.
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