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TitleStructural and mechanistic insights into the inhibition of Plasmodium falciparum MDR1.
Journal, issue, pagesNat Commun, Year 2026
Publish dateMay 27, 2026
AuthorsZiyan Zhao / Jialu Li / Xinye Wang / Xiaofeng Liu / Nan Wang / Hanwen Xu / Cantao Quan / Yu Gao / Jing Zhang / Xiang Wang / Li Guo / Nobutaka Kato / Dong Deng / Xin Jiang /
PubMed AbstractMalaria, caused by the parasite Plasmodium falciparum, remains a significant global health threat, with multidrug resistance posing a major challenge to treatment. The P-glycoprotein homolog P. ...Malaria, caused by the parasite Plasmodium falciparum, remains a significant global health threat, with multidrug resistance posing a major challenge to treatment. The P-glycoprotein homolog P. falciparum Multidrug Resistance Protein 1 (PfMDR1) is a key determinant of resistance to first-line antimalarials like mefloquine (MFQ) and chloroquine. ACT-451840, a clinical phase I drug, has been developed as an antimalarial candidate, but its mechanism of action and interaction with drug resistance markers remain to be fully understood. Here, we present the cryo-electron microscopy structure of PfMDR1 in complex with ACT-451840, determined at a resolution of 3.42 Å. The structure reveals that ACT-451840 binds within the central cavity and locks PfMDR1 in an inward-open conformation, inhibiting its basal ATPase activity. A structural comparison of the ACT-451840-bound state with the previously reported MFQ-bound state provides a molecular explanation for how ACT-451840 resistance mutations can lead to the sensitization of MFQ. Furthermore, a comparative structural analysis and biochemical characterization with human ABCB1 reveal the selective mechanism of ACT-451840 against PfMDR1. Our findings provide a structural basis for the inhibitory mechanism of ACT-451840, which may inform the future development of antimalarial candidates targeting PfMDR1.
External linksNat Commun / PubMed:42203772
MethodsEM (single particle)
Resolution3.43 Å
Structure data

66192

9ws4

EMDB-66192, PDB-9ws4:
Cyro-EM structure of the ACT-451840-bound PfMDR1
Method: EM (single particle) / Resolution: 3.43 Å

Chemicals

PDB-1eyj:
FRUCTOSE-1,6-BISPHOSPHATASE COMPLEX WITH AMP, MAGNESIUM, FRUCTOSE-6-PHOSPHATE AND PHOSPHATE (T-STATE)

Source
  • plasmodium falciparum 3d7 (eukaryote)
KeywordsTRANSPORT PROTEIN / ATP-binding cassette transporter / ATPase activity / membrane proteins

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