The <i>Plasmodium falciparum</i> NCR1 transporter is an antimalarial target that exports cholesterol from the parasite’s plasma membrane

Malaria, a devastating parasitic infection, is the leading cause of death in many developing countries. Unfortunately, the most deadliest causative agent of malaria, <i>Plasmodium falciparum</i>, has developed resistance to nearly all currently available antimalarial drugs. The <i>P. falciparum</i> Niemann-Pick type C1-related (PfNCR1) transporter has been identified as a druggable target, but its structure and detailed molecular mechanism are not yet available. Here, we present three structures of PfNCR1 with and without the functional inhibitor MMV009108 at resolutions between 2.98 and 3.81 Å using single-particle cryo-electron microscopy (cryo-EM), suggesting that PfNCR1 binds cholesterol and forms a cholesterol transport tunnel to modulate the composition of the parasite plasma membrane. Cholesterol efflux assays show that PfNCR1 is an exporter capable of extruding cholesterol from the membrane. Additionally, the inhibition mechanism of MMV009108 appears to be due to a direct blockage of PfNCR1, preventing this transporter from shuttling cholesterol.

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Publication Details

Journal
Science Advances
Published
2024-12-18
DOI
https://doi.org/10.1126/sciadv.adq6651
Citations
4
Primary Topic
Malaria Research and Control
Type
article
Field-Weighted Citation Impact
2.17
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article

The Plasmodium falciparum NCR1 transporter is an antimalarial target that exports cholesterol from the parasite’s plasma membrane

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4 citations
Science Advances
Malaria Research and Control
2.17
article

The Plasmodium falciparum NCR1 transporter is an antimalarial target that exports cholesterol from the parasite’s plasma membrane

Masaru Miyagi, Jenna Oberstaller, Han Xu, Youwei Zhang, Marios Tringides, Daniel E. Goldberg, Marvin T. Nieman, Meinan Lyu, Johannes von Lintig, Zhemin Zhang, John H. Adams, Xinran Geng, Edward Yu, Sepalika Bandara, Eva S. Istvan, Meng Cui, William D. Gregor
article en
4 citations

Abstract

Malaria, a devastating parasitic infection, is the leading cause of death in many developing countries. Unfortunately, the most deadliest causative agent of malaria, <i>Plasmodium falciparum</i>, has developed resistance to nearly all currently available antimalarial drugs. The <i>P. falciparum</i> Niemann-Pick type C1-related (PfNCR1) transporter has been identified as a druggable target, but its structure and detailed molecular mechanism are not yet available. Here, we present three structures of PfNCR1 with and without the functional inhibitor MMV009108 at resolutions between 2.98 and 3.81 Å using single-particle cryo-electron microscopy (cryo-EM), suggesting that PfNCR1 binds cholesterol and forms a cholesterol transport tunnel to modulate the composition of the parasite plasma membrane. Cholesterol efflux assays show that PfNCR1 is an exporter capable of extruding cholesterol from the membrane. Additionally, the inhibition mechanism of MMV009108 appears to be due to a direct blockage of PfNCR1, preventing this transporter from shuttling cholesterol.

Science AdvancesVol. 10(51)
Northeastern University (US), Washington University in St. Louis (US), University of South Florida (US), University School (US), Case Western Reserve University (US)
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Openalex Percentile: Top 11%
Malaria Research and Control
2.17
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