L McGillewie, Soliman Mahmoud E
Molecular Modelling & Drug Design Research Group, School of Health Sciences, University of KwaZulu-Natal, Westville, Durban 4001, South Africa.
Mol Biosyst. 2016 Apr 26;12(5):1457-67. doi: 10.1039/c6mb00077k.
Plasmepsin V belongs to the plasmepsin family of aspartic proteases. PlmV is unique compared to other plasmepsins, as this membrane bound aspartic protease resides in the endoplasmic reticulum and is responsible for the cleavage of PEXEL tagged proteins destined for export outside of the host red blood cell. Plasmepsin V is highly conserved throughout the Plasmodium species, and is essential to the survival of the parasite. Recently, two potent inhibitors of Plmv have been identified, WEHI-916 and WEHI-842. Of these inhibitors, WEHI-842 has a higher binding affinity for P. vivax PlmV, and a crystal structure of PlmV in complex with WEHI-842 has recently been resolved (). The structure of PlmV is unique compared to other plasmepsins; it is stabilised internally by seven disulfide bonds, a NAP1 insert/fold is associated with the movement of the flap covering the active site and a highly conserved helix-turn-helix is situated towards the C-terminus. Flap motion and dynamics play an important role in enzyme selectivity and function. To better understand the impact of ligand binding on the flap dynamics, molecular dynamic simulations and post-dynamic analysis were employed in the present study on PlmV in complex with WEHI-842. Previously defined parameters, which accurately accounted for the opening and closing of the active site, were used to assess the conformational changes induced in the absence and presence of WEHI-842. From the simulations it can be seen that inhibitor binding significantly reduces the flexibility and mobility of not only the flap and flexible loop but areas outside of the active site. Ligand binding leads to the formation of a more stable compact structure. This being said, there is a possibility of reducing the flexibility even further with potentially more lethal effects on the plasmodium parasite. We believe that results presented herein would assist researchers in the discovery of potent PlmV inhibitors as potential antimalarial therapies.
疟原虫天冬氨酸蛋白酶V属于天冬氨酸蛋白酶的疟原虫天冬氨酸蛋白酶家族。与其他疟原虫天冬氨酸蛋白酶相比，疟原虫天冬氨酸蛋白酶V具有独特性，因为这种膜结合天冬氨酸蛋白酶存在于内质网中，负责切割注定要输出到宿主红细胞外的带有PEXEL标签的蛋白质。疟原虫天冬氨酸蛋白酶V在整个疟原虫物种中高度保守，对寄生虫的生存至关重要。最近，已鉴定出两种强效的疟原虫天冬氨酸蛋白酶V抑制剂，即WEHI-916和WEHI-842。在这些抑制剂中，WEHI-842对间日疟原虫疟原虫天冬氨酸蛋白酶V具有更高的结合亲和力，并且最近解析了疟原虫天冬氨酸蛋白酶V与WEHI-842复合物的晶体结构（）。与其他疟原虫天冬氨酸蛋白酶相比，疟原虫天冬氨酸蛋白酶V的结构独特；它通过七个二硫键在内部稳定，一个NAP1插入/折叠与覆盖活性位点的瓣片的移动相关，并且一个高度保守的螺旋-转角-螺旋位于C末端附近。瓣片运动和动力学在酶的选择性和功能中起重要作用。为了更好地理解配体结合对瓣片动力学的影响，本研究对疟原虫天冬氨酸蛋白酶V与WEHI-842的复合物进行了分子动力学模拟和动力学后分析。使用先前定义的、能准确解释活性位点打开和关闭的参数来评估在不存在和存在WEHI-842时诱导的构象变化。从模拟中可以看出，抑制剂结合不仅显著降低了瓣片和柔性环的灵活性和流动性，还降低了活性位点之外区域的灵活性和流动性。配体结合导致形成更稳定的紧密结构。话虽如此，有可能进一步降低灵活性，对疟原虫寄生虫产生潜在的更致命影响。我们相信本文给出的结果将有助于研究人员发现强效的疟原虫天冬氨酸蛋白酶V抑制剂作为潜在的抗疟疗法。
