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- PDB-8jwf: Cryo-EM structure of Plasmodium falciparum multidrug resistance p... -

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Basic information

Entry
Database: PDB / ID: 8jwf
TitleCryo-EM structure of Plasmodium falciparum multidrug resistance protein 1 with H1 helix in complex with MFQ
ComponentsMultidrug resistance protein 1P-glycoprotein
KeywordsTRANSPORT PROTEIN / Plasmodium falciparum / Multidrug resistance protein 1 / ABC transporter / MFQ complex
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
Mefloquine / Multidrug resistance protein 1
Similarity search - Component
Biological speciesPlasmodium falciparum (malaria parasite P. falciparum)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.64 Å
AuthorsLi, M. / Si, K.
Funding support China, 1items
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, 2023Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Aug 30, 2023Provider: 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)163,1432
Polymers162,7651
Non-polymers3781
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Multidrug resistance protein 1 / P-glycoprotein


Mass: 162764.812 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Plasmodium falciparum (isolate 3D7) (eukaryote)
Gene: PF3D7_0523000 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q7K6A5
#2: Chemical ChemComp-YMZ / Mefloquine / Mefloquine


Mass: 378.312 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H16F6N2O / Feature type: SUBJECT OF INVESTIGATION / Comment: medication*YM
Has ligand of interestY

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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: Plasmodium falciparum multidrug resistance protein 1 in complex with MFQ
Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Plasmodium falciparum 3D7 (eukaryote)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.4
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: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2500 nm / Nominal defocus min: 1200 nm
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.64 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 153425 / Symmetry type: POINT

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