9hb0

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

spinqualitylabelsall models 9hb0, resolution 1.70Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9hb0 is a 1 chain structure with sequence from Plasmodium falciparum 3D7. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.7Å Ligands: A1ITU, SO4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function PLM10_PLAF7 During the asexual blood stage, processes key proteins essential for merozoite egress and invasion of host erythrocytes (PubMed:29074775, PubMed:32109369). Cleaves and activates proteases SUB1 and SUB2 (PubMed:29074775, PubMed:32109369, PubMed:38969256). May process members of the EBL and Rh protein families (PubMed:32109369). Also cleaves apical membrane protein AMA1 (PubMed:29074775). During the mosquito vector stage and probably in ookinetes, cleaves CelTOS (PubMed:29074775). Publication Abstract from PubMed 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 A 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. Structural Plasticity of Plasmodium falciparum Plasmepsin X to Accommodate Binding of Potent Macrocyclic Hydroxyethylamine Inhibitors.,Withers-Martinez C, George R, Ogrodowicz R, Kunzelmann S, Purkiss AG, Kjaer S, Walker PA, Kovada V, Jirgensons A, Blackman MJ J Mol Biol. 2025 Mar 3;437(10):169062. doi: 10.1016/j.jmb.2025.169062. PMID:40043835 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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