Rahul C N, Shiva Krishna K, Pawar Atul P, Bai Meera, Kumar Vijay, Phadke Sandhya, Rajesh Vidya
a Department of Biological Sciences , Birla Institute of Technology and Science, Pilani , Hyderabad Campus , Andhra Pradesh , India .
J Biomol Struct Dyn. 2014 Apr;32(4):580-90. doi: 10.1080/07391102.2013.782824. Epub 2013 Apr 13.
Plasmodium vivax malaria is geographically the most widely distributed and prevalent form of human malaria. The development of drug resistance by the parasite to existing drugs necessitates higher focus to explore and identify new drug targets. Plasmodial proteases have key roles in parasite biology and are involved in nutritional uptake, egress from infected reticulocytes, and invasion of the new target erythrocytes. Serine repeat antigens (SERA) of Plasmodium are parasite proteases that remain attractive drug targets and are important vaccine candidates due to their high expression profiles in the blood stages. SERA proteins have a unique putative papain-like cysteine protease motif that has either serine or cysteine in its active site. In P. vivax, PvSERA4 is the highest transcribed member of this multigene family. In this study, we have investigated the genetic polymorphism of PvSERA4 central protease domain and deduced its 3D model by homology modeling and also performed MD simulations to acquire refined protein structure. Sequence analysis of protease domain of PvSERA4 from Indian field isolates reveals that the central domain is highly conserved. The high sequence conservation of the PvSERA4 enzyme domain coupled with its high expression raises the possibility of it having a critical role in parasite biology and hence, being a reliable target for new selective inhibitor-based antimalarial chemotherapeutics. The 3D model showed the presence of an unusual antiparallel Beta hairpin motif between catalytic residues similar to hemoglobin binding motif of Plasmodial hemoglobinases. Our PvSERA4 model will aid in designing structure-based inhibitors against this enzyme.
间日疟原虫疟疾在地理上是人类疟疾分布最广、最为流行的形式。该寄生虫对现有药物产生耐药性，这就需要更加关注探索和确定新的药物靶点。疟原虫蛋白酶在寄生虫生物学中发挥关键作用，参与营养摄取、从受感染的网织红细胞中逸出以及侵入新的靶红细胞。疟原虫的丝氨酸重复抗原（SERA）是寄生虫蛋白酶，由于其在血液阶段的高表达水平，仍然是有吸引力的药物靶点和重要的疫苗候选物。SERA蛋白具有独特的假定木瓜蛋白酶样半胱氨酸蛋白酶基序，其活性位点含有丝氨酸或半胱氨酸。在间日疟原虫中，PvSERA4是这个多基因家族中转录水平最高的成员。在本研究中，我们研究了PvSERA4中央蛋白酶结构域的遗传多态性，通过同源建模推导其三维模型，并进行分子动力学模拟以获得优化的蛋白质结构。对来自印度野外分离株的PvSERA4蛋白酶结构域的序列分析表明，中央结构域高度保守。PvSERA4酶结构域的高序列保守性及其高表达增加了它在寄生虫生物学中发挥关键作用的可能性，因此，它可能成为基于新型选择性抑制剂的抗疟化疗药物的可靠靶点。三维模型显示，在催化残基之间存在一个不寻常的反平行β发夹基序，类似于疟原虫血红蛋白酶的血红蛋白结合基序。我们构建的PvSERA4模型将有助于设计针对该酶的基于结构的抑制剂。
