9WS4

Cyro-EM structure of the ACT-451840-bound PfMDR1

This is a non-PDB format compatible entry.

Summary for 9WS4

• Entry DOI: 10.2210/pdb9ws4/pdb
• EMDB information: 66192
• Descriptor: Multidrug resistance protein 1, ACT-451840 (2 entities in total)
• Functional Keywords: atp-binding cassette transporter, atpase activity, membrane proteins, transport protein
• Biological source: Plasmodium falciparum 3D7
• Total number of polymer chains: 1
• Total formula weight: 167410.85

Authors

Zhao, Z.,Li, J.,Wang, X.,Liu, X.,Wang, N.,Xu, H.,Quan, C.,Wang, X.,Kato, N.,Deng, D.,Jing, X. (deposition date: 2025-09-12, release date: 2026-06-10)

Primary citation

Zhao, Z.,Li, J.,Wang, X.,Liu, X.,Wang, N.,Xu, H.,Quan, C.,Gao, Y.,Zhang, J.,Wang, X.,Guo, L.,Kato, N.,Deng, D.,Jiang, X.
Structural and mechanistic insights into the inhibition of Plasmodium falciparum MDR1.
Nat Commun, 2026

PubMed 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.

PubMed: 42203772
DOI: 10.1038/s41467-026-73692-y

Experimental method

ELECTRON MICROSCOPY (3.43 Å)