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- PDB-9ws4: Cyro-EM structure of the ACT-451840-bound PfMDR1 -

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Basic information

Entry
Database: PDB / ID: 9ws4
TitleCyro-EM structure of the ACT-451840-bound PfMDR1
ComponentsMultidrug resistance protein 1
KeywordsTRANSPORT PROTEIN / ATP-binding cassette transporter / ATPase activity / membrane proteins
Function / homology
Function and homology information


Recycling of bile acids and salts / Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol / Atorvastatin ADME / Prednisone ADME / ABC-family protein mediated transport / food vacuole / ABC-type xenobiotic transporter / vacuolar membrane / ABC-type xenobiotic transporter activity / ATPase-coupled transmembrane transporter activity ...Recycling of bile acids and salts / Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol / Atorvastatin ADME / Prednisone ADME / ABC-family protein mediated transport / food vacuole / ABC-type xenobiotic transporter / vacuolar membrane / ABC-type xenobiotic transporter activity / ATPase-coupled transmembrane transporter activity / transmembrane transport / ATP hydrolysis activity / ATP binding / membrane / metal ion binding
Similarity search - Function
Type 1 protein exporter / ABC transporter transmembrane region / ABC transporter type 1, transmembrane domain / ABC transporter integral membrane type-1 fused domain profile. / ABC transporter type 1, transmembrane domain superfamily / ABC transporter-like, conserved site / ABC transporters family signature. / ABC transporter / ABC transporter-like, ATP-binding domain / ATP-binding cassette, ABC transporter-type domain profile. ...Type 1 protein exporter / ABC transporter transmembrane region / ABC transporter type 1, transmembrane domain / ABC transporter integral membrane type-1 fused domain profile. / ABC transporter type 1, transmembrane domain superfamily / ABC transporter-like, conserved site / ABC transporters family signature. / ABC transporter / ABC transporter-like, ATP-binding domain / ATP-binding cassette, ABC transporter-type domain profile. / ATPases associated with a variety of cellular activities / AAA+ ATPase domain / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
: / Multidrug resistance protein 1
Similarity search - Component
Biological speciesPlasmodium falciparum 3D7 (eukaryote)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.43 Å
AuthorsZhao, Z. / Li, J. / Wang, X. / Liu, X. / Wang, N. / Xu, H. / Quan, C. / Wang, X. / Kato, N. / Deng, D. / Jing, X.
Funding support China, 2items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)32501079 China
Natural Science Foundation of Sichuan Province2023NSFSC0017 China
CitationJournal: Nat Commun / Year: 2026
Title: Structural and mechanistic insights into the inhibition of Plasmodium falciparum MDR1.
Authors: Ziyan 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 /
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. ...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.
History
DepositionSep 12, 2025Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Jun 10, 2026Provider: repository / Type: Initial release
Revision 1.0Jun 10, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Jun 10, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jun 10, 2026Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jun 10, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Jun 10, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Multidrug resistance protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)167,4112
Polymers166,6601
Non-polymers7511
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein Multidrug resistance protein 1 / PfMDR1 / P-glycoprotein homolog / PGH1


Mass: 166659.875 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Plasmodium falciparum 3D7 (eukaryote) / Gene: PF3D7_0523000 / Production host: Homo sapiens (human)
References: UniProt: Q7K6A5, ABC-type xenobiotic transporter
#2: Chemical ChemComp-A1EYJ / ACT-451840 / 3-(4-tert-butylphenyl)-N-[(2S)-1-[4-[(4-cyanophenyl)methyl]piperazin-1-yl]-1-oxidanylidene-3-phenyl-propan-2-yl]-N-[[4-(4-ethanoylpiperazin-1-yl)phenyl]methyl]prop-2-enamide / (S,E)-N-(4-(4-acetylpiperazin-1-yl)benzyl)3-(4-(tert-butyl)phenyl)-N-(1-(4-(4-cyanobenzyl)piperazin-1-yl)-1oxo-3-phenylpropan-2-yl)acrylamide


Mass: 750.970 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C47H54N6O3 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Genes encoding full-length PfMDR1 were synthesized and subcloned into a modified pCAG vector with an N-terminal twin-strep tag.
Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Plasmodium falciparum 3D7 (eukaryote)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 8
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 1500 nm
Image recordingElectron dose: 47.12 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

EM software
IDNameVersionCategory
1cryoSPARCparticle selection
2PHENIX1.20.1_4487:model refinement
13Coot3D reconstruction
CTF correctionType: NONE
3D reconstructionResolution: 3.43 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 337745 / Symmetry type: POINT
Atomic model building
IDProtocol
1AB INITIO MODEL
2
3
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0119908
ELECTRON MICROSCOPYf_angle_d1.20913360
ELECTRON MICROSCOPYf_dihedral_angle_d8.0961308
ELECTRON MICROSCOPYf_chiral_restr0.0651527
ELECTRON MICROSCOPYf_plane_restr0.0071669

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