8CDM

Plasmodium falciparum Myosin A full-length, post-rigor state complexed to the inhibitor KNX-002

Summary for 8CDM

• Entry DOI: 10.2210/pdb8cdm/pdb
• Related: 8A12 8CDQ
• Descriptor: Myosin-A, Myosin A tail domain interacting protein, Myosin essential light chain ELC, ... (7 entities in total)
• Functional Keywords: malaria, plasmodium falciparum, myosin a, knx-002, antimalarial treatment, molecular motors, motor protein
• Biological source: Plasmodium falciparum (malaria parasite P. falciparum); More
• Total number of polymer chains: 3
• Total formula weight: 132321.63

Authors

Moussaoui, D.,Robblee, J.P.,Robert-Paganin, J.,Auguin, D.,Fisher, F.,Fagnant, P.M.,MacFarlane, J.E.,Mueller-Dieckmann, C.,Baum, J.,Trybus, K.M.,Houdusse, A. (deposition date: 2023-01-31, release date: 2024-02-21, Last modification date: 2024-10-16)

Primary citation

Moussaoui, D.,Robblee, J.P.,Robert-Paganin, J.,Auguin, D.,Fisher, F.,Fagnant, P.M.,Macfarlane, J.E.,Schaletzky, J.,Wehri, E.,Mueller-Dieckmann, C.,Baum, J.,Trybus, K.M.,Houdusse, A.
Mechanism of small molecule inhibition of Plasmodium falciparum myosin A informs antimalarial drug design.
Nat Commun, 14:3463-3463, 2023

PubMed Abstract: Malaria results in more than 500,000 deaths per year and the causative Plasmodium parasites continue to develop resistance to all known agents, including different antimalarial combinations. The class XIV myosin motor PfMyoA is part of a core macromolecular complex called the glideosome, essential for Plasmodium parasite mobility and therefore an attractive drug target. Here, we characterize the interaction of a small molecule (KNX-002) with PfMyoA. KNX-002 inhibits PfMyoA ATPase activity in vitro and blocks asexual blood stage growth of merozoites, one of three motile Plasmodium life-cycle stages. Combining biochemical assays and X-ray crystallography, we demonstrate that KNX-002 inhibits PfMyoA using a previously undescribed binding mode, sequestering it in a post-rigor state detached from actin. KNX-002 binding prevents efficient ATP hydrolysis and priming of the lever arm, thus inhibiting motor activity. This small-molecule inhibitor of PfMyoA paves the way for the development of alternative antimalarial treatments.

PubMed: 37308472
DOI: 10.1038/s41467-023-38976-7

Experimental method

X-RAY DIFFRACTION (2.35 Å)