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- EMDB-36674: Cryo-EM structure of Plasmodium falciparum multidrug resistance p... -

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Basic information

Entry
Database: EMDB / ID: EMD-36674
TitleCryo-EM structure of Plasmodium falciparum multidrug resistance protein 1 in the apo state with H1 helix
Map data
Sample
  • Complex: Plasmodium falciparum multidrug resistance protein 1 in apo state
    • Protein or peptide: Multidrug resistance protein 1P-glycoprotein
KeywordsPlasmodium falciparum / Multidrug resistance protein 1 / ABC transporter / Apo state / 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 / Antigen Presentation: Folding, assembly and peptide loading of class I MHC / ABC-family proteins mediated transport / food vacuole / ATPase-coupled transmembrane transporter activity / ABC-type transporter activity ...xenobiotic-transporting ATPase / Recycling of bile acids and salts / Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol / Atorvastatin ADME / Prednisone ADME / Antigen Presentation: Folding, assembly and peptide loading of class I MHC / 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: 3.19 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 28, 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_36674.png

Downloads & links

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Map

FileDownload / File: emd_36674.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: 0.35
Minimum - Maximum-2.0437636 - 3.5726812
Average (Standard dev.)-0.0025246735 (±0.077449135)
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_36674_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_36674_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 apo state

EntireName: Plasmodium falciparum multidrug resistance protein 1 in apo state
Components
  • Complex: Plasmodium falciparum multidrug resistance protein 1 in apo state
    • Protein or peptide: Multidrug resistance protein 1P-glycoprotein

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Supramolecule #1: Plasmodium falciparum multidrug resistance protein 1 in apo state

SupramoleculeName: Plasmodium falciparum multidrug resistance protein 1 in apo state
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
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: 162.764812 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: GGGGSMGKEQ KEKKDGNLSI KEEVEKELNK KSTAELFRKI KNEKISFFLP FKCLPAQHRK LLFISFVCAV LSGGTLPFFI SVFGVILKN MNLGDDINPI ILSLVSIGLV QFILSMISSY CMDVITSKIL KTLKLEYLRS VFYQDGQFHD NNPGSKLRSD L DFYLEQVS ...String:
GGGGSMGKEQ KEKKDGNLSI KEEVEKELNK KSTAELFRKI KNEKISFFLP FKCLPAQHRK LLFISFVCAV LSGGTLPFFI SVFGVILKN MNLGDDINPI ILSLVSIGLV QFILSMISSY CMDVITSKIL KTLKLEYLRS VFYQDGQFHD NNPGSKLRSD L DFYLEQVS SGIGTKFITI FTYASSFLGL YIWSLIKNAR LTLCITCVFP LIYVCGVICN KKVKLNKKTS LLYNNNTMSI IE EALMGIR TVASYCGEKT ILNKFNLSET FYSKYILKAN FVEALHIGLI NGLILVSYAF GFWYGTRIII NSATNQYPNN DFN GASVIS ILLGVLISMF MLTIILPNIT EYMKALEATN SLYEIINRKP LVENNDDGET LPNIKKIEFK NVRFHYDTRK DVEI YKDLS FTLKEGKTYA FVGESGCGKS TILKLIERLY DPTEGDIIVN DSHNLKDINL KWWRSKIGVV SQDPLLFSNS IKNNI KYSL YSLKDLEAME NYYEENTNDT YENKNFSLIS NSMTSNELLE MKKEYQTIKD SDVVDVSKKV LIHDFVSSLP DKYDTL VGS NASKLSGGQK QRISIARAIM RNPKILILDE ATSSLDNKSE YLVQKTINNL KGNENRITII IAHRLSTIRY ANTIFVL SN RERSDNNNNN NNDDNNNNNN NNNNKINNEG SYIIEQGTHD SLMKNKNGIY HLMINNQKIS SNKSSNNGND NGSDNKSS A YKDSDTGNDA DNMNSLSIHE NENISNNRNC KNTAENEKEE KVPFFKRMFR RKKKAPNNLR IIYKEIFSYK KDVTIIFFS ILVAGGLYPV FALLYARYVS TLFDFANLEY NSNKYSIYIL LIAIAMFISE TLKNYYNNKI GEKVEKTMKR RLFENILYQE MSFFDQDKN TPGVLSAHIN RDVHLLKTGL VNNIVIFSHF IMLFLVSMVM SFYFCPIVAA VLTFIYFINM RVFAVRARLT K SKEIEKKE NMSSGVFAFS SDDEMFKDPS FLIQEAFYNM HTVINYGLED YFCNLIEKAI DYKNKGQKRR IIVNAALWGF SQ SAQLFIN SFAYWFGSFL IKRGTILVDD FMKSLFTFIF TGSYAGKLMS LKGDSENAKL SFEKYYPLMI RKSNIDVRDD GGI RINKNL IKGKVDIKDV NFRYISRPNV PIYKNLSFTC DSKKTTAIVG ETGSGKSTFM NLLLRFYDLK NDHIILKNDM TNFQ DYQNN NNNSLVLKNV NEFSNQSGSA EDYTVFNNNG EILLDDINIC DYNLRDLRNL FSIVSQEPML FNMSIYENIK FGRED ATLE DVKRVSKFAA IDEFIESLPN KYDTNVGPYG KSLSGGQKQR IAIARALLRE PKILLLDEAT SSLDSNSEKL IEKTIV DIK DKADKTIITI AHRIASIKRS DKIVVFNNPD RNGTFVQSHG THDELLSAQD GIYKKYVKLA K

UniProtKB: Multidrug resistance protein 1

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

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Image processing

Startup modelType of model: NONE
Initial angle assignmentType: OTHER
Final angle assignmentType: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.19 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 217767

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