Structural and mechanistic insights into the inhibition of Plasmodium falciparum MDR1

  • Nat Commun. 2026 May 27. doi: 10.1038/s41467-026-73692-y.
Ziyan Zhao  #  1  2 ,  Jialu Li  #  3 ,  Xinye Wang  #  1  2 ,  Xiaofeng Liu  1  2 ,  Nan Wang  4 ,  Hanwen Xu  4 ,  Cantao Quan  1  2 ,  Yu Gao  1  2 ,  Jing Zhang  1  2 ,  Xiang Wang  3 ,  Li Guo  3 ,  Nobutaka Kato  5 ,  Dong Deng  6  7 ,  Xin Jiang  8  9
Affiliations
  • 1. Genetic Diseases Key Laboratory of Sichuan Province, Department of Medical Genetics, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, PR China.
  • 2. Sichuan-Chongqing Joint Key Laboratory of Pathology and Laboratory Medicine, Jinfeng Laboratory, Chongqing, PR China.
  • 3. Department of Obstetrics, Key Laboratory of Birth Defects and Related Disease of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second Hospital, Sichuan University, Chengdu, China.
  • 4. State Key Laboratory of Membrane Biology, Beijing Advanced Innovation Center for Structural Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China.
  • 5. Institute of Tropical Medicine, Nagasaki University, Nagasaki, Japan.
  • 6. Department of Obstetrics, Key Laboratory of Birth Defects and Related Disease of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second Hospital, Sichuan University, Chengdu, China. [email protected].
  • 7. Development and Related Diseases of Women and Children Key Laboratory of Sichuan Province, Sichuan University, Chengdu, China. [email protected].
  • 8. Genetic Diseases Key Laboratory of Sichuan Province, Department of Medical Genetics, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, PR China. [email protected].
  • 9. Sichuan-Chongqing Joint Key Laboratory of Pathology and Laboratory Medicine, Jinfeng Laboratory, Chongqing, PR China. [email protected].
  • # Contributed equally.
PMID: 42203772 DOI: 10.1038/s41467-026-73692-y
Abstract

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.

Products