دورية أكاديمية
Mechanism of small molecule inhibition of Plasmodium falciparum myosin A informs antimalarial drug design
| العنوان: | Mechanism of small molecule inhibition of Plasmodium falciparum myosin A informs antimalarial drug design |
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| المؤلفون: | Moussaoui, Dihia, Robblee, James, Robert-Paganin, Julien, Auguin, Daniel, Fisher, Fabio, Fagnant, Patricia, Macfarlane, Jill, Schaletzky, Julia, Wehri, Eddie, Mueller-Dieckmann, Christoph, Baum, Jake, Trybus, Kathleen, Houdusse, Anne |
| المساهمون: | Centre National de la Recherche Scientifique (CNRS), Biologie Cellulaire et Cancer, Institut Curie Paris -Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Physiologie, Ecologie et Environnement (P2E), Université d'Orléans (UO)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE) |
| المصدر: | ISSN: 2041-1723. |
| بيانات النشر: | HAL CCSD Nature Publishing Group |
| سنة النشر: | 2023 |
| المجموعة: | Université d'Orléans: HAL |
| مصطلحات موضوعية: | [SDV]Life Sciences [q-bio] |
| الوصف: | International audience ; 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. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| العلاقة: | info:eu-repo/semantics/altIdentifier/pmid/37308472; hal-04267663; https://hal.science/hal-04267663Test; https://hal.science/hal-04267663/documentTest; https://hal.science/hal-04267663/file/Moussaoui_2023_CRAC.pdfTest; PUBMED: 37308472; WOS: 001007854800017 |
| DOI: | 10.1038/s41467-023-38976-7 |
| الإتاحة: | https://doi.org/10.1038/s41467-023-38976-7Test https://hal.science/hal-04267663Test https://hal.science/hal-04267663/documentTest https://hal.science/hal-04267663/file/Moussaoui_2023_CRAC.pdfTest |
| حقوق: | http://creativecommons.org/licenses/byTest/ ; info:eu-repo/semantics/OpenAccess |
| رقم الانضمام: | edsbas.FE5203E4 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1038/s41467-023-38976-7 |
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