9HB0

Crystal structure of Plasmodium falciparum Plasmepsin X in complex with the hydroxyethylamine drug 7k.

This is a non-PDB format compatible entry.

Summary for 9HB0

• Entry DOI: 10.2210/pdb9hb0/pdb
• Descriptor: Plasmepsin X, (4S)-4-[(1R)-2-[2-(3-methoxyphenyl)propan-2-ylamino]-1-oxidanyl-ethyl]-16-propyl-3,16-diazatricyclo[16.3.1.1^{6,10}]tricosa-1(21),6,8,10(23),18(22),19-hexaene-2,17-dione, SULFATE ION, ... (4 entities in total)
• Functional Keywords: aspartyl protease, hydroxyethylamine inhibitor, complex, non-covalent., hydrolase
• Biological source: Plasmodium falciparum 3D7
• Total number of polymer chains: 1
• Total formula weight: 41108.61

Authors

Withers-Martinez, C.,George, R.,Ogrodowicz, R.,Kunzelmann, S.,Purkiss, A.,Kjaer, S.,Walker, P.,Kovada, V.,Jirgensons, A.,Blackman, M.J. (deposition date: 2024-11-05, release date: 2025-03-19, Last modification date: 2025-03-26)

Primary citation

Withers-Martinez, C.,George, R.,Ogrodowicz, R.,Kunzelmann, S.,Purkiss, A.G.,Kjaer, S.,Walker, P.A.,Kovada, V.,Jirgensons, A.,Blackman, M.J.
Structural Plasticity of Plasmodium falciparum Plasmepsin X to Accommodate Binding of Potent Macrocyclic Hydroxyethylamine Inhibitors.
J.Mol.Biol., 437:169062-169062, 2025

PubMed Abstract: 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 1.7 Å 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.

PubMed: 40043835
DOI: 10.1016/j.jmb.2025.169062

Experimental method

X-RAY DIFFRACTION (1.7 Å)