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- EMDB-21355: CryoEM Structure of the PfFNT-inhibitor complex -

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Basic information

Entry
Database: EMDB / ID: EMD-21355
TitleCryoEM Structure of the PfFNT-inhibitor complex
Map data
Sample
  • Complex: PfFNT
    • Protein or peptide: Formate-nitrite transporter
  • Ligand: (2R)-2-hydroxy-7-methoxy-2-(pentafluoroethyl)-2,3-dihydro-4H-1-benzopyran-4-one
KeywordsTransporter / MEMBRANE PROTEIN
Function / homology
Function and homology information


high-affinity secondary active nitrite transmembrane transporter activity / lactate transmembrane transport / nitrite transport / lactate:proton symporter activity / plasma membrane
Similarity search - Function
Formate and nitrite transporters signature 2. / Formate/nitrite transporter / Formate/nitrite transporter, conserved site / Formate/nitrite transporter / Aquaporin-like
Similarity search - Domain/homology
Formate-nitrite transporter
Similarity search - Component
Biological speciesPlasmodium falciparum 3D7 (eukaryote) / Plasmodium falciparum (isolate 3D7) (eukaryote)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.78 Å
AuthorsSu CC / Lyu M
CitationJournal: EMBO Rep / Year: 2021
Title: Structural basis of transport and inhibition of the Plasmodium falciparum transporter PfFNT.
Authors: Meinan Lyu / Chih-Chia Su / James W Kazura / Edward W Yu /
Abstract: The intra-erythrocyte stage of P. falciparum relies primarily on glycolysis to generate adenosine triphosphate (ATP) and the energy required to support growth and reproduction. Lactic acid, a ...The intra-erythrocyte stage of P. falciparum relies primarily on glycolysis to generate adenosine triphosphate (ATP) and the energy required to support growth and reproduction. Lactic acid, a metabolic byproduct of glycolysis, is potentially toxic as it lowers the pH inside the parasite. Plasmodium falciparum formate-nitrite transporter (PfFNT), a 34-kDa transmembrane protein, has been identified as a novel drug target as it exports lactate from inside the parasite to the surrounding parasitophorous vacuole within the erythrocyte cytosol. The structure and detailed molecular mechanism of this membrane protein are not yet available. Here we present structures of PfFNT in the absence and presence of the functional inhibitor MMV007839 at resolutions of 2.56 Å and 2.78 Å using single-particle cryo-electron microscopy. Genetic analysis and transport assay indicate that PfFNT is able to transfer lactate across the membrane. Combined, our data suggest a stepwise displacement mechanism for substrate transport. The PfFNT membrane protein is capable of picking up lactate ions from the parasite's cytosol, converting them to lactic acids and then exporting these acids into the extracellular space.
History
DepositionFeb 5, 2020-
Header (metadata) releaseMar 18, 2020-
Map releaseFeb 3, 2021-
UpdateMar 6, 2024-
Current statusMar 6, 2024Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.4
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.4
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6vqr
  • Surface level: 0.4
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_21355.png

Downloads & links

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Map

FileDownload / File: emd_21355.map.gz / Format: CCP4 / Size: 3.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesX (Sec.)Y (Row.)Z (Col.)
1.08 Å/pix.
x 77 pix.
= 83.16 Å		1.08 Å/pix.
x 95 pix.
= 102.6 Å		1.08 Å/pix.
x 112 pix.
= 120.96 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

generated in cubic-lattice coordinate

Voxel sizeX=Y=Z: 1.08 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.26 / Movie #1: 0.4
Minimum - Maximum-3.3660645 - 5.3511996
Average (Standard dev.)-0.000000000000006 (±0.31187943)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderZYX
Origin10492110
Dimensions9511277
Spacing7795112
CellA: 83.16 Å / B: 102.600006 Å / C: 120.96001 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.081.081.08
M x/y/z7795112
origin x/y/z0.0000.0000.000
length x/y/z83.160102.600120.960
α/β/γ90.00090.00090.000
start NX/NY/NZ11010492
NX/NY/NZ7795112
MAP C/R/S321
start NC/NR/NS92104110
NC/NR/NS1129577
D min/max/mean-3.3665.351-0.000

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Supplemental data

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Sample components

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Entire : PfFNT

EntireName: PfFNT
Components
  • Complex: PfFNT
    • Protein or peptide: Formate-nitrite transporter
  • Ligand: (2R)-2-hydroxy-7-methoxy-2-(pentafluoroethyl)-2,3-dihydro-4H-1-benzopyran-4-one

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Supramolecule #1: PfFNT

SupramoleculeName: PfFNT / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Plasmodium falciparum 3D7 (eukaryote)

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Macromolecule #1: Formate-nitrite transporter

MacromoleculeName: Formate-nitrite transporter / type: protein_or_peptide / ID: 1 / Number of copies: 5 / Enantiomer: LEVO
Source (natural)Organism: Plasmodium falciparum (isolate 3D7) (eukaryote) / Strain: isolate 3D7
Molecular weightTheoretical: 34.492281 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MPPNNSKYVL DPVSIKSVCG GEESYIRCVE YGKKKAHYSN LNLLAKAILA GMFVGLCAHA SGIAGGLFYY HKLREIVGAS MSVFVYGFT FPIAFMCIIC TGSDLFTGNT LAVTMALYEK KVKLLDYLRV MTISLFGNYV GAVSFAFFVS YLSGAFTNVH A VEKNHFFQ ...String:
MPPNNSKYVL DPVSIKSVCG GEESYIRCVE YGKKKAHYSN LNLLAKAILA GMFVGLCAHA SGIAGGLFYY HKLREIVGAS MSVFVYGFT FPIAFMCIIC TGSDLFTGNT LAVTMALYEK KVKLLDYLRV MTISLFGNYV GAVSFAFFVS YLSGAFTNVH A VEKNHFFQ FLNDIAEKKV HHTFVECVSL AVGCNIFVCL AVYFVLTLKD GAGYVFSVFF AVYAFAIAGY EHIIANIYTL NI ALMVNTK ITVYQAYIKN LLPTLLGNYI AGAIVLGLPL YFIYKEHYYN FERSKRDNND AQMKSLSIEL RN

UniProtKB: Formate-nitrite transporter

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Macromolecule #2: (2R)-2-hydroxy-7-methoxy-2-(pentafluoroethyl)-2,3-dihydro-4H-1-be...

MacromoleculeName: (2R)-2-hydroxy-7-methoxy-2-(pentafluoroethyl)-2,3-dihydro-4H-1-benzopyran-4-one
type: ligand / ID: 2 / Number of copies: 5 / Formula: R7M
Molecular weightTheoretical: 312.189 Da
Chemical component information

ChemComp-R7M:
(2R)-2-hydroxy-7-methoxy-2-(pentafluoroethyl)-2,3-dihydro-4H-1-benzopyran-4-one

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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

Concentration0.5 mg/mL
BufferpH: 7.5
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV
DetailsThis sample was monodisperse.

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 29.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: SPOT SCAN / Imaging mode: BRIGHT FIELD
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: EMDB MAP
Final reconstructionNumber classes used: 1 / Resolution.type: BY AUTHOR / Resolution: 2.78 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 141224
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION

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Atomic model buiding 1

RefinementProtocol: AB INITIO MODEL
Output model

PDB-6vqr:
CryoEM Structure of the PfFNT-inhibitor complex

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