Issue 5, 2016

The binding landscape of plasmepsin V and the implications for flap dynamics

Abstract

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 (4ZL4). 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.

Graphical abstract: The binding landscape of plasmepsin V and the implications for flap dynamics

Supplementary files

Article information

Article type
Paper
Submitted
30 Janv. 2016
Accepted
02 Marts 2016
First published
02 Marts 2016

Mol. BioSyst., 2016,12, 1457-1467

The binding landscape of plasmepsin V and the implications for flap dynamics

M. L. and M. E. Soliman, Mol. BioSyst., 2016, 12, 1457 DOI: 10.1039/C6MB00077K

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