Biology subjects

Robblee, J. P.

Publications and source records attributed to Robblee, J. P..

3 recordsLinked to original sources

bioRxiv2026

Plasmodium falciparum Myosin B is a slow motor optimized for force generation

Malaria is a disease caused by apicomplexan parasites of the genus Plasmodium. These organisms express two atypical class-XIV myosins: Myosin A (MyoA), a core component of the glideosome expressed throughout the entire lifecycle, and Myosin B (MyoB), which is restricted to invasive stages and localizes to the apical region. Here, we determine the crystal structure of Plasmodium falciparum MyoB (PfMyoB) in the Rigor state and identify its essential light chain as the same subunit bound to MyoA. Combining structural analysis, molecular dynamics simulations and in vitro kinetic and motility assays, we show that PfMyoB is a slow motor optimized for force production during invasion. The N-terminal extensions of PfMyoA and PfMyoB exert distinct effects on each motor s mechanochemistry. Altogether, these findings reveal how Plasmodium myosins have evolved specialized functions during the complex parasite lifecycle and provide insight into developing multi-target inhibitors of erythrocytic invasion based on the PfMyoA inhibitor KNX-002.

biophysics↗

bioRxiv2022

Mechanism of small molecule inhibition of Plasmodium falciparum myosin A informs antimalarial drug design

Malaria is responsible for more than a half million deaths per year. The Plasmodium parasites responsible continue to develop resistance to all known agents, despite treatment with different antimalarial combinations. The atypical Myosin A 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, X-ray crystallography and molecular dynamics, we demonstrate that KNX-002 targets a novel pocket in PfMyoA, sequestering it in a post-rigor state detached from actin. KNX-002 binding affects Mg2+ coordination near ATP, preventing ATP hydrolysis and thus inhibiting motor activity. This first-in-class small-molecule inhibitor of PfMyoA paves the way for developing a new generation of antimalarial treatments.

molecular biology↗

bioRxiv2020

Structure of Full Length Plasmodium Myosin A and its light chain PfELC, dual targets against malaria parasite pathogenesis

Parasites from the genus Plasmodium are the causative agents of malaria. The mobility, infectivity and ultimately pathogenesis of this parasite relies on a macromolecular complex, called the glideosome. At the core of the glideosome is an essential and divergent Myosin A motor (PfMyoA), a first order drug target against malaria. Here we present the full-length structure of PfMyoA in two states of its motor cycle. We report novel interactions that are essential for motor priming and the mode of recognition of its two light chains (PfELC and MTIP) by two degenerate IQ motifs. Kinetic and motility assays using PfMyoA variants, along with molecular dynamics, demonstrate how specific priming and atypical sequence adaptations tune the motor’s mechano-chemical properties. Supported by evidence for an essential role of the PfELC in malaria pathogenesis, these structures provide a blueprint for the design of future antimalarials targeting both the glideosome motor and its regulatory elements.HighlightsThe first structures of the full length PfMyoA motor in two states of its motor cycle.A unique priming of the PfMyoA lever arm results from specific lever arm/motor domain interactions, which allows for a larger powerstroke to enhance speed.Sequence adaptations within the motor domain and degenerate IQ motifs in the lever arm dictate PfMyoA motor properties.PfELC is essential for blood cell invasion and is a weak link in the assembly of a fully functional motor, providing a second novel target for antimalarial drug design.Competing Interest StatementThe authors have declared no competing interest.View Full Text

biochemistry↗