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- PDB-8v1g: plasmodium falciparum Niemann-Pick type C1-related protein bound ... -

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Basic information

Entry
Database: PDB / ID: 8v1g
Titleplasmodium falciparum Niemann-Pick type C1-related protein bound with MMV009108
ComponentsNiemann-Pick type C1-related protein
KeywordsMEMBRANE PROTEIN / Niemann-Pick type C1-related protein / NCR1 / cholesterol transporter / plasmodium falciparum
Function / homologyProtein patched/dispatched / : / Patched SSD / Sterol-sensing domain (SSD) profile. / Sterol-sensing domain / membrane / CHOLESTEROL / : / Niemann-Pick type C1-related protein
Function and homology information
Biological speciesPlasmodium falciparum 3D7 (eukaryote)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.98 Å
AuthorsZhang, Z. / Lyu, M.
Funding support United States, 1items
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 20, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 20, 2024Provider: repository / Type: Initial release
Revision 1.1Mar 19, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
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Assembly

Deposited unit
A: Niemann-Pick type C1-related protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)171,7505
Polymers170,5051
Non-polymers1,2454
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

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


Mass: 170505.406 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Plasmodium falciparum 3D7 (eukaryote) / Gene: PF3D7_0107500 / Production host: Homo sapiens (human) / References: UniProt: Q8I266
#2: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0
#3: Chemical ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H46O
#4: Chemical ChemComp-Y6F / MMV009108 / 4-[2-(3,4-dimethylanilino)-1,3-thiazol-4-yl]-N,N-diethylbenzene-1-sulfonamide


Mass: 415.572 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H25N3O2S2 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationY

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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: Niemann-Pick type C1-related protein / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Plasmodium falciparum 3D7 (eukaryote)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
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 FIELD / Nominal magnification: 81000 X / Nominal defocus max: 1500 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 40.5 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 5798543
3D reconstructionResolution: 2.98 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 82204 / Symmetry type: POINT

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