Structural plasticity of Plasmodium falciparum plasmepsin X to accommodate binding of potent macrocyclic hydroxyethylamine inhibitors
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Chrislaine Withers-Martinez Roger George Roksana Ogrodowicz Simone Kunzelmann Andrew G Purkiss Svend Kjaer Philip Walker Vadims Kovada Aigars Jirgensons Michael BlackmanAbstract
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.
Journal details
Journal
Journal of Molecular Biology
Volume
437
Issue number
10
Pages
169062
Available online
Publication date
Full text links
Publisher website (DOI)
10.1016/j.jmb.2025.169062
Europe PubMed Central
40043835
Pubmed
40043835
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