Work

Structural Plasticity of Plasmodium falciparum Plasmepsin X to Accommodate Binding of Potent Macrocyclic Hydroxyethylamine Inhibitors

Year: 2025

Type: article

Abstract: • Malaria parasite egress is regulated by the essential aspartic protease PMX. • Macrocyclic hydroxyethylamine compound 7k is a potent PMX inhibitor. • We determine the 1.7Å crystallographic structure of the PMX-7k complex. • Upon 7k binding the PMX active site adopts a novel, partially closed conformation. • Docking of a 7k derivative highlights a ligand stabilising region of the S3 pocket. Plasmodium falciparum plasmepsin X (PMX) has become a target of choice for the development of new antimalarial drugs due to its essential role across the parasite life cycle. Here we describe the 1.7Å crystallographic structure of PMX noncovalently bound to a potent macrocyclic peptidomimetic inhibitor ( 7k ) possessing a hydroxyethylamine (HEA) scaffold. Upon 7k binding, the enzyme adopts a novel conformation, with significant involvement of the S2’S2 loop (M526-H536) and the S2 flap (F311-G314). This results in partial closure of the active site with widespread interactions in both the prime (S’) and the non-prime (S) sites of PMX. The catalytic aspartate residues D266 and D467 directly interact with the HEA pharmacophore. Docking of a 7k derivative, compound 7a , highlights a region in the S3 pocket near the S3 flexible loop (H242-F248) that may be key for ligand stabilisation. The dynamic nature of PMX and its propensity to undergo distinct types of induced fit upon inhibitor binding enables generation of potent inhibitors that target this essential malarial aspartic protease.

Source: Journal of Molecular Biology

DOI: 10.1016/j.jmb.2025.169062