Agrawal Megha R, Ozarkar Aarti D, Gupta Shipra, Deobagkar Dileep N, Deobagkar Deepti D
Bioinformatics Centre & Department of Zoology, Center of Advanced Studies, University of Pune, Pune 411007, India.
Mol Biosyst. 2014 Jul 29;10(9):2466-79. doi: 10.1039/c4mb00274a.
The variant surface antigen PfEMP1 (Plasmodium falciparum erythrocyte membrane protein 1) encoded by the polymorphic multi-copy var gene family plays an important role in parasite biology and the host-parasite interactions. Sequestration and antigenic variation is an essential component in the survival and pathogenesis of Plasmodium falciparum and contributes to chronic infection. The DBLα domain of PfEMP1 is a potential target for immuno-epidemiological studies and has been visualized as a vaccine candidate against severe malaria. Specific host receptors like heparin, heparan sulphate, blood group A and complement receptor 1 have been reported to bind the DBLα domain. Although heparin has been experimentally shown to disrupt the parasite-host interaction and effectively disrupt rosetting, the binding sites for the DBLα domain and the mechanism behind heparin-mediated rosette inhibition have not been elucidated. In this study, 3D structures and epitopes of the DBLα domain in 3D7 and in two Indian isolates have been predicted and compared. We have carried out docking studies on DBLα domains with human GAG receptors (heparin and heparan sulphate) to predict the strength of association between the protein-ligand interactions. The DBLα domain structures showed extensive diversity and polymorphism in their binding sites. The docking results indicate that heparin binds more effectively with high affinity as compared to heparan sulphate with some common interacting residues. These common residues can play an important role in rosetting and will aid in the designing of inhibitors specific to the interactions between DBLα and heparin or heparan sulphate would be important in malaria treatment. Thus it may lead to the development of novel interference strategies to block red blood cell invasion and provide protection against malaria.
由多态性多拷贝var基因家族编码的可变表面抗原PfEMP1（恶性疟原虫红细胞膜蛋白1）在寄生虫生物学和宿主-寄生虫相互作用中起重要作用。滞留和抗原变异是恶性疟原虫生存和发病机制的重要组成部分，并导致慢性感染。PfEMP1的DBLα结构域是免疫流行病学研究的潜在靶点，并且已被视为抗重症疟疾的候选疫苗。据报道，肝素、硫酸乙酰肝素、A血型和补体受体1等特定宿主受体可与DBLα结构域结合。尽管实验表明肝素可破坏寄生虫与宿主的相互作用并有效破坏红细胞凝聚，但DBLα结构域的结合位点以及肝素介导的红细胞凝聚抑制背后的机制尚未阐明。在本研究中，已预测并比较了3D7和两个印度分离株中DBLα结构域的三维结构和表位。我们对DBLα结构域与人GAG受体（肝素和硫酸乙酰肝素）进行了对接研究，以预测蛋白质-配体相互作用之间的结合强度。DBLα结构域结构在其结合位点显示出广泛的多样性和多态性。对接结果表明，与硫酸乙酰肝素相比，肝素以高亲和力更有效地结合，且存在一些共同的相互作用残基。这些共同残基可能在红细胞凝聚中起重要作用，并有助于设计针对DBLα与肝素或硫酸乙酰肝素之间相互作用的抑制剂，这在疟疾治疗中很重要。因此，这可能会导致开发新的干扰策略来阻断红细胞入侵并提供抗疟疾保护。
