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- EMDB-36684: Cryo-EM structure of the outward-facing Plasmodium falciparum mul... -

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Basic information

Entry
Database: EMDB / ID: EMD-36684
TitleCryo-EM structure of the outward-facing Plasmodium falciparum multidrug resistance protein 1
Map data
Sample
  • Complex: Plasmodium falciparum multidrug resistance protein 1 in the outward-facing conformation
    • Protein or peptide: Multidrug resistance protein 1
  • Ligand: ADENOSINE-5'-TRIPHOSPHATE
  • Ligand: MAGNESIUM ION
KeywordsPlasmodium falciparum / Multidrug resistance protein 1 / ABC transporter / Outward-facing / TRANSPORT PROTEIN
Function / homology
Function and homology information


xenobiotic-transporting ATPase / Recycling of bile acids and salts / Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol / Atorvastatin ADME / Prednisone ADME / ABC-family proteins mediated transport / food vacuole / ATPase-coupled transmembrane transporter activity / ABC-type transporter activity / transmembrane transport ...xenobiotic-transporting ATPase / Recycling of bile acids and salts / Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol / Atorvastatin ADME / Prednisone ADME / ABC-family proteins mediated transport / food vacuole / ATPase-coupled transmembrane transporter activity / ABC-type transporter activity / transmembrane transport / ATP hydrolysis activity / ATP binding / membrane
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 (isolate 3D7) (eukaryote)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.94 Å
AuthorsLi M / Si K
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)32171209 China
CitationJournal: Proc Natl Acad Sci U S A / Year: 2023
Title: The structure of multidrug resistance protein 1 reveals an N-terminal regulatory domain.
Authors: Kaixue Si / Xishuo He / Liping Chen / Anqi Zhang / Changyou Guo / Minghui Li /
Abstract: multidrug resistance protein 1 (PfMDR1), an adenosine triphosphate (ATP)-binding cassette (ABC) transporter on the digestive vacuole (DV) membrane of the parasite, is associated with the resistance ... multidrug resistance protein 1 (PfMDR1), an adenosine triphosphate (ATP)-binding cassette (ABC) transporter on the digestive vacuole (DV) membrane of the parasite, is associated with the resistance to antimalarial drugs. To understand the mechanisms of PfMDR1, we determined the cryo-electron microscopy structures of this transporter in different states. The transporter in the apo state shows an inward-facing conformation with a large cavity opening to the cytoplasm. Upon ATP binding and dimerization of the nucleotide-binding domains (NBDs), PfMDR1 displays an outward-facing conformation with a cavity toward the DV lumen. Drug resistance-associated mutations were investigated in both structures for their effects, and Y184F was identified as an allosteric activity-enhancing mutation. The amphiphilic substrate-binding site of PfMDR1 was revealed by the complex structure with the antimalarial drug mefloquine and confirmed by mutagenesis studies. Remarkably, a helical structure was found to hinder NBD dimerization and inhibit PfMDR1 activity. The location of this regulatory domain in the N terminus is different from the well-studied R domain in the internal linker region of other ABC transporter family members. The lack of the phosphorylation site of this domain also suggests a different regulation mechanism.
History
DepositionJun 29, 2023-
Header (metadata) releaseAug 30, 2023-
Map releaseAug 30, 2023-
UpdateAug 30, 2023-
Current statusAug 30, 2023Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_36684.png

Downloads & links

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Map

FileDownload / File: emd_36684.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.1 Å
Density
Contour LevelBy AUTHOR: 0.8
Minimum - Maximum-2.3438456 - 4.091941
Average (Standard dev.)-0.0019136074 (±0.11496123)
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: #2

Fileemd_36684_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_36684_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Plasmodium falciparum multidrug resistance protein 1 in the outwa...

EntireName: Plasmodium falciparum multidrug resistance protein 1 in the outward-facing conformation
Components
  • Complex: Plasmodium falciparum multidrug resistance protein 1 in the outward-facing conformation
    • Protein or peptide: Multidrug resistance protein 1
  • Ligand: ADENOSINE-5'-TRIPHOSPHATE
  • Ligand: MAGNESIUM ION

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Supramolecule #1: Plasmodium falciparum multidrug resistance protein 1 in the outwa...

SupramoleculeName: Plasmodium falciparum multidrug resistance protein 1 in the outward-facing conformation
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Plasmodium falciparum (isolate 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
Source (natural)Organism: Plasmodium falciparum (isolate 3D7) (eukaryote)
Molecular weightTheoretical: 158.420828 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: GGGGSEKISF FLPFKCLPAQ HRKLLFISFV CAVLSGGTLP FFISVFGVIL KNMNLGDDIN PIILSLVSIG LVQFILSMIS SYCMDVITS KILKTLKLEY LRSVFYQDGQ FHDNNPGSKL RSDLDFYLEQ VSSGIGTKFI TIFTYASSFL GLYIWSLIKN A RLTLCITC ...String:
GGGGSEKISF FLPFKCLPAQ HRKLLFISFV CAVLSGGTLP FFISVFGVIL KNMNLGDDIN PIILSLVSIG LVQFILSMIS SYCMDVITS KILKTLKLEY LRSVFYQDGQ FHDNNPGSKL RSDLDFYLEQ VSSGIGTKFI TIFTYASSFL GLYIWSLIKN A RLTLCITC VFPLIYVCGV ICNKKVKLNK KTSLLYNNNT MSIIEEALMG IRTVASYCGE KTILNKFNLS ETFYSKYILK AN FVEALHI GLINGLILVS YAFGFWYGTR IIINSATNQY PNNDFNGASV ISILLGVLIS MFMLTIILPN ITEYMKALEA TNS LYEIIN RKPLVENNDD GETLPNIKKI EFKNVRFHYD TRKDVEIYKD LSFTLKEGKT YAFVGESGCG KSTILKLIER LYDP TEGDI IVNDSHNLKD INLKWWRSKI GVVSQDPLLF SNSIKNNIKY SLYSLKDLEA MENYYEENTN DTYENKNFSL ISNSM TSNE LLEMKKEYQT IKDSDVVDVS KKVLIHDFVS SLPDKYDTLV GSNASKLSGG QKQRISIARA IMRNPKILIL DQATSS LDN KSEYLVQKTI NNLKGNENRI TIIIAHRLST IRYANTIFVL SNRERSDNNN NNNNDDNNNN NNNNNNKINN EGSYIIE QG THDSLMKNKN GIYHLMINNQ KISSNKSSNN GNDNGSDNKS SAYKDSDTGN DADNMNSLSI HENENISNNR NCKNTAEN E KEEKVPFFKR MFRRKKKAPN NLRIIYKEIF SYKKDVTIIF FSILVAGGLY PVFALLYARY VSTLFDFANL EYNSNKYSI YILLIAIAMF ISETLKNYYN NKIGEKVEKT MKRRLFENIL YQEMSFFDQD KNTPGVLSAH INRDVHLLKT GLVNNIVIFS HFIMLFLVS MVMSFYFCPI VAAVLTFIYF INMRVFAVRA RLTKSKEIEK KENMSSGVFA FSSDDEMFKD PSFLIQEAFY N MHTVINYG LEDYFCNLIE KAIDYKNKGQ KRRIIVNAAL WGFSQSAQLF INSFAYWFGS FLIKRGTILV DDFMKSLFTF IF TGSYAGK LMSLKGDSEN AKLSFEKYYP LMIRKSNIDV RDDGGIRINK NLIKGKVDIK DVNFRYISRP NVPIYKNLSF TCD SKKTTA IVGETGSGKS TFMNLLLRFY DLKNDHIILK NDMTNFQDYQ NNNNNSLVLK NVNEFSNQSG SAEDYTVFNN NGEI LLDDI NICDYNLRDL RNLFSIVSQE PMLFNMSIYE NIKFGREDAT LEDVKRVSKF AAIDEFIESL PNKYDTNVGP YGKSL SGGQ KQRIAIARAL LREPKILLLD QATSSLDSNS EKLIEKTIVD IKDKADKTII TIAHRIASIK RSDKIVVFNN PDRNGT FVQ SHGTHDELLS AQDGIYKKYV KLAK

UniProtKB: Multidrug resistance protein 1

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Macromolecule #2: ADENOSINE-5'-TRIPHOSPHATE

MacromoleculeName: ADENOSINE-5'-TRIPHOSPHATE / type: ligand / ID: 2 / Number of copies: 2 / Formula: ATP
Molecular weightTheoretical: 507.181 Da
Chemical component information

ChemComp-ATP:
ADENOSINE-5'-TRIPHOSPHATE / ATP, energy-carrying molecule*YM

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Macromolecule #3: MAGNESIUM ION

MacromoleculeName: MAGNESIUM ION / type: ligand / ID: 3 / Number of copies: 2 / Formula: MG
Molecular weightTheoretical: 24.305 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: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.2 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.94 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 270432
Initial angle assignmentType: OTHER
Final angle assignmentType: OTHER

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