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- EMDB-42854: plasmodium falciparum Niemann-Pick type C1-related protein form I -

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Basic information

Entry
Database: EMDB / ID: EMD-42854
Titleplasmodium falciparum Niemann-Pick type C1-related protein form I
Map data
Sample
  • Complex: Niemann-Pick type C1-related protein
    • Protein or peptide: Niemann-Pick type C1-related protein
  • Ligand: CHOLESTEROL
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
KeywordsNiemann-Pick type C1-related protein / NCR1 / cholesterol transporter / plasmodium falciparum / MEMBRANE PROTEIN
Function / homology: / Protein patched/dispatched / Patched SSD / Sterol-sensing domain (SSD) profile. / Sterol-sensing domain / membrane / Niemann-Pick type C1-related protein
Function and homology information
Biological speciesPlasmodium falciparum 3D7 (eukaryote)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.11 Å
AuthorsZhang Z / Lyu M
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID) United States
CitationJournal: Sci Adv / Year: 2024
Title: The NCR1 transporter is an antimalarial target that exports cholesterol from the parasite's plasma membrane.
Authors: Zhemin Zhang / Meinan Lyu / Xu Han / Sepalika Bandara / Meng Cui / Eva S Istvan / Xinran Geng / Marios L Tringides / William D Gregor / Masaru Miyagi / Jenna Oberstaller / John H Adams / ...Authors: Zhemin Zhang / Meinan Lyu / Xu Han / Sepalika Bandara / Meng Cui / Eva S Istvan / Xinran Geng / Marios L Tringides / William D Gregor / Masaru Miyagi / Jenna Oberstaller / John H Adams / Youwei Zhang / Marvin T Nieman / Johannes von Lintig / Daniel E Goldberg / Edward W Yu /
Abstract: Malaria, a devastating parasitic infection, is the leading cause of death in many developing countries. Unfortunately, the most deadliest causative agent of malaria, , has developed resistance to ...Malaria, a devastating parasitic infection, is the leading cause of death in many developing countries. Unfortunately, the most deadliest causative agent of malaria, , has developed resistance to nearly all currently available antimalarial drugs. The Niemann-Pick type C1-related (PfNCR1) transporter has been identified as a druggable target, but its structure and detailed molecular mechanism are not yet available. Here, we present three structures of PfNCR1 with and without the functional inhibitor MMV009108 at resolutions between 2.98 and 3.81 Å using single-particle cryo-electron microscopy (cryo-EM), suggesting that PfNCR1 binds cholesterol and forms a cholesterol transport tunnel to modulate the composition of the parasite plasma membrane. Cholesterol efflux assays show that PfNCR1 is an exporter capable of extruding cholesterol from the membrane. Additionally, the inhibition mechanism of MMV009108 appears to be due to a direct blockage of PfNCR1, preventing this transporter from shuttling cholesterol.
History
DepositionNov 17, 2023-
Header (metadata) releaseNov 13, 2024-
Map releaseNov 13, 2024-
UpdateMar 19, 2025-
Current statusMar 19, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_42854.png

Downloads & links

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Map

FileDownload / File: emd_42854.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
1.07 Å/pix.
x 300 pix.
= 321. Å		1.07 Å/pix.
x 300 pix.
= 321. Å		1.07 Å/pix.
x 300 pix.
= 321. Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.07 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.1
Minimum - Maximum-0.5345329 - 0.86740035
Average (Standard dev.)-0.0013758554 (±0.022817781)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 321.00003 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_42854_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_42854_half_map_2.map
Projections & Slices
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Histogram

Histogram (log scale)

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Sample components

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Entire : Niemann-Pick type C1-related protein

EntireName: Niemann-Pick type C1-related protein
Components
  • Complex: Niemann-Pick type C1-related protein
    • Protein or peptide: Niemann-Pick type C1-related protein
  • Ligand: CHOLESTEROL
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: Niemann-Pick type C1-related protein

SupramoleculeName: Niemann-Pick type C1-related protein / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Plasmodium falciparum 3D7 (eukaryote)

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Macromolecule #1: Niemann-Pick type C1-related protein

MacromoleculeName: Niemann-Pick type C1-related protein / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Plasmodium falciparum 3D7 (eukaryote)
Molecular weightTheoretical: 170.505406 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MFVKNFIHKL KELKQKSLDK FANLLYDYGG YVYDRPCTFI ICSLICCLLL TCGFYFKEHE KDIYKLYSIS NSYAYETNET INDFFYKSR RCFILVESNV NLLKPKILRE LQKFEEGTKD IEVDLSEINE CKTNSELPPE QSHVAKELYK TLIQRSEENL K SGKINGSL ...String:
MFVKNFIHKL KELKQKSLDK FANLLYDYGG YVYDRPCTFI ICSLICCLLL TCGFYFKEHE KDIYKLYSIS NSYAYETNET INDFFYKSR RCFILVESNV NLLKPKILRE LQKFEEGTKD IEVDLSEINE CKTNSELPPE QSHVAKELYK TLIQRSEENL K SGKINGSL FDYSDLDENG KSVLSLAGKE NNDDTLIEGD NKNDEETSAN NNNNEDDNNE DDNNEDDNNE DDNNENDNNN NN EDDNNND DDDDEDNEEE DEEKQKSLRE KLYRKIYEML KKKKENIVLD ENNPNVNFTD YKDDVFYPYQ YIPPMLIKAD RCK LQNVFG DKNLNIDLRE ASDGLKKQIT YTLEDICEKK YGDCNFSSLF LYYEKGNGYI DYPIKVDNLD FYVNRRTYKE MMFK GILGN MVYEKSGSKY IIKSANAIMT VIPLLNSHTY EPYALAYEKK LIDYVRFYNL DDIIQDEETN DDNDPFIRFH VFTDR SLED EVDRISKIDN LTRLLLLIGV LLIFMYALFN NVTSVLYRSK PLCAVMGIFC GFLGFLSGSG FLYFLGVKSV PPAETV PFL VIGVGVDDVF VILNSYSLLF MVKDNKKRIQ MCLKDSALAI TVTTLTNIIA FLISAISPFY SICAFSLFTA SSLFFGY LM VLTFLLSFLC IEAKLEKKKR NIFTGTFHLF RSIFMKSSKK NKKENKENNI HDDGDNDNDE KKKDLSLEVK NNEDDYEN I SIYEWIHNLY LFEESINKKK KNAALVYASN NGMSSNLNNV NEDGFPNPSK IVSMEDVKKR NIKKDDAYIN KEDEEGGGY YNKDDNKKKD ILGKKQKKNN NNVTLVSKKG EDNELDVYYE NLDEKTNDKY KMNNIKSSKL KYDNDKKDGA IINNRPSSDE EYKEEKDKN KINILNDVFN DITIKPNENI LLDRGDVIKS SGYDSSYNDL QSSSLPNPSS NEVLNKTTMV YNETDLKDNK K EIKSSKKN VKDIKKSDMI HDDTYDIINS NNKNILLSSN EINNNSNNTN KFNNNSTELA TKDTQQFING HDKNIYLLSS HD NALFYKY IYEEPKGNIG KYFRSLVKNY YVPFLSSRFG KTIVYIMFTI IIAMSIYGCT LMKKGIKYDK AFPVDSYVRR FTT AKIKYF PDFGDFIEVY YFDKHFINKY RGLEKNTKEA ASSFLYSDLT DRQIMNSPKI NKNVHWENTN LQEELINMHN TLES QEFVT SVANGFTFFL NKNKSSLRKE NPQEFYEIFA NWLKKDFVGN LFKNDFVFLN GKLVAWRFHY FQKNVDDSEI SSKWL KACK QITKLENHNV QMVCFHLSSI FNETDESIIE VTLINLGITI LTILVVTAYI IKGFYSCVII ALIIFLIDLC IFGFMC LCG ITMNIISMVI LVLSVGFSID HTSHIVQAFS HSMGRTRDEK MKESLHLMIG PVLHSGLSTW FVISTLFFSN KDFTVIF FQ TLSLVLFFSI TFSSMFLPVL LSSFGPLH

UniProtKB: Niemann-Pick type C1-related protein

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Macromolecule #2: CHOLESTEROL

MacromoleculeName: CHOLESTEROL / type: ligand / ID: 2 / Number of copies: 1 / Formula: CLR
Molecular weightTheoretical: 386.654 Da
Chemical component information

ChemComp-CLR:
CHOLESTEROL

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Macromolecule #3: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 3 / Number of copies: 2 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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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: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 35.86 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.5 µm / Nominal defocus min: 0.8 µm / Nominal magnification: 81000
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 6977953
Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.11 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 63097
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION
FSC plot (resolution estimation)

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