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- EMDB-66192: Cyro-EM structure of the ACT-451840-bound PfMDR1 -

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Basic information

Entry
Database: EMDB / ID: EMD-66192
TitleCyro-EM structure of the ACT-451840-bound PfMDR1
Map data
Sample
  • Complex: Genes encoding full-length PfMDR1 were synthesized and subcloned into a modified pCAG vector with an N-terminal twin-strep tag.
    • Protein or peptide: Multidrug resistance protein 1
  • Ligand: ACT-451840
KeywordsATP-binding cassette transporter / ATPase activity / membrane proteins / TRANSPORT PROTEIN
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)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.43 Å
AuthorsZhao Z / Li J / Wang X / Liu X / Wang N / Xu H / Quan C / Kato N / Deng D / Jing X
Funding support China, 2 items
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, 2025-
Header (metadata) releaseJun 10, 2026-
Map releaseJun 10, 2026-
UpdateJun 10, 2026-
Current statusJun 10, 2026Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_66192.png

Downloads & links

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Map

FileDownload / File: emd_66192.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.1 Å/pix.
x 256 pix.
= 281.6 Å		1.1 Å/pix.
x 256 pix.
= 281.6 Å		1.1 Å/pix.
x 256 pix.
= 281.6 Å

Surface

Projections

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Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.1 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.15
Minimum - Maximum-0.42751688 - 1.1236906
Average (Standard dev.)0.00053891237 (±0.023904264)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 281.6 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_66192_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_66192_half_map_2.map
Projections & Slices
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Histogram (log scale)

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Sample components

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Entire : Genes encoding full-length PfMDR1 were synthesized and subcloned ...

EntireName: Genes encoding full-length PfMDR1 were synthesized and subcloned into a modified pCAG vector with an N-terminal twin-strep tag.
Components
  • Complex: Genes encoding full-length PfMDR1 were synthesized and subcloned into a modified pCAG vector with an N-terminal twin-strep tag.
    • Protein or peptide: Multidrug resistance protein 1
  • Ligand: ACT-451840

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Supramolecule #1: Genes encoding full-length PfMDR1 were synthesized and subcloned ...

SupramoleculeName: Genes encoding full-length PfMDR1 were synthesized and subcloned into a modified pCAG vector with an N-terminal twin-strep tag.
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Plasmodium falciparum 3D7 (eukaryote)

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Macromolecule #1: Multidrug resistance protein 1

MacromoleculeName: Multidrug resistance protein 1 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO / EC number: ABC-type xenobiotic transporter
Source (natural)Organism: Plasmodium falciparum 3D7 (eukaryote)
Molecular weightTheoretical: 166.659875 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MGSWSHPQFE KGGGSGGGSG GSAWSHPQFE KSGDEVDASS GRMGKEQKEK KDGNLSIKEE VEKELNKKST AELFRKIKNE KISFFLPFK CLPAQHRKLL FISFVCAVLS GGTLPFFISV FGVILKNMNL GDDINPIILS LVSIGLVQFI LSMISSYCMD V ITSKILKT ...String:
MGSWSHPQFE KGGGSGGGSG GSAWSHPQFE KSGDEVDASS GRMGKEQKEK KDGNLSIKEE VEKELNKKST AELFRKIKNE KISFFLPFK CLPAQHRKLL FISFVCAVLS GGTLPFFISV FGVILKNMNL GDDINPIILS LVSIGLVQFI LSMISSYCMD V ITSKILKT LKLEYLRSVF YQDGQFHDNN PGSKLRSDLD FYLEQVSSGI GTKFITIFTY ASSFLGLYIW SLIKNARLTL CI TCVFPLI YVCGVICNKK VKLNKKTSLL YNNNTMSIIE EALMGIRTVA SYCGEKTILN KFNLSETFYS KYILKANFVE ALH IGLING LILVSYAFGF WYGTRIIINS ATNQYPNNDF NGASVISILL GVLISMFMLT IILPNITEYM KALEATNSLY EIIN RKPLV ENNDDGETLP NIKKIEFKNV RFHYDTRKDV EIYKDLSFTL KEGKTYAFVG ESGCGKSTIL KLIERLYDPT EGDII VNDS HNLKDINLKW WRSKIGVVSQ DPLLFSNSIK NNIKYSLYSL KDLEAMENYY EENTNDTYEN KNFSLISNSM TSNELL EMK KEYQTIKDSD VVDVSKKVLI HDFVSSLPDK YDTLVGSNAS KLSGGQKQRI SIARAIMRNP KILILDEATS SLDNKSE YL VQKTINNLKG NENRITIIIA HRLSTIRYAN TIFVLSNRER SDNNNNNNND DNNNNNNNNN NKINNEGSYI IEQGTHDS L MKNKNGIYHL MINNQKISSN KSSNNGNDNG SDNKSSAYKD SDTGNDADNM NSLSIHENEN ISNNRNCKNT AENEKEEKV PFFKRMFRRK KKAPNNLRII YKEIFSYKKD VTIIFFSILV AGGLYPVFAL LYARYVSTLF DFANLEYNSN KYSIYILLIA IAMFISETL KNYYNNKIGE KVEKTMKRRL FENILYQEMS FFDQDKNTPG VLSAHINRDV HLLKTGLVNN IVIFSHFIML F LVSMVMSF YFCPIVAAVL TFIYFINMRV FAVRARLTKS KEIEKKENMS SGVFAFSSDD EMFKDPSFLI QEAFYNMHTV IN YGLEDYF CNLIEKAIDY KNKGQKRRII VNAALWGFSQ SAQLFINSFA YWFGSFLIKR GTILVDDFMK SLFTFIFTGS YAG KLMSLK GDSENAKLSF EKYYPLMIRK SNIDVRDDGG IRINKNLIKG KVDIKDVNFR YISRPNVPIY KNLSFTCDSK KTTA IVGET GSGKSTFMNL LLRFYDLKND HIILKNDMTN FQDYQNNNNN SLVLKNVNEF SNQSGSAEDY TVFNNNGEIL LDDIN ICDY NLRDLRNLFS IVSQEPMLFN MSIYENIKFG REDATLEDVK RVSKFAAIDE FIESLPNKYD TNVGPYGKSL SGGQKQ RIA IARALLREPK ILLLDEATSS LDSNSEKLIE KTIVDIKDKA DKTIITIAHR IASIKRSDKI VVFNNPDRNG TFVQSHG TH DELLSAQDGI YKKYVKLAK

UniProtKB: Multidrug resistance protein 1

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Macromolecule #2: ACT-451840

MacromoleculeName: ACT-451840 / type: ligand / ID: 2 / Number of copies: 1 / Formula: A1EYJ
Molecular weightTheoretical: 750.97 Da

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 47.12 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.5 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: NONE
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.43 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: Coot / Number images used: 337745
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION

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Atomic model buiding 1

RefinementProtocol: AB INITIO MODEL
Output model

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

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