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- PDB-7mxy: Cryo-EM structure of PfFNT-inhibitor complex -

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Basic information

Entry
Database: PDB / ID: 7mxy
TitleCryo-EM structure of PfFNT-inhibitor complex
ComponentsFormate-nitrite transporter
KeywordsTRANSPORT PROTEIN/INHIBITOR / PfFNT / Lactate transporter / PfFNT-MMV007839 complex / TRANSPORT PROTEIN-INHIBITOR complex
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 / Glycerol uptake facilitator protein / Glycerol uptake facilitator protein. / Aquaporin-like / Up-down Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-HV6 / Formate-nitrite transporter
Similarity search - Component
Biological speciesPlasmodium falciparum (malaria parasite P. falciparum)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.18 Å
AuthorsYu, E.W. / Su, C. / 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: 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
DepositionMay 19, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 8, 2021Provider: repository / Type: Initial release
Revision 1.1May 29, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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Assembly

Deposited unit
A: Formate-nitrite transporter
B: Formate-nitrite transporter
C: Formate-nitrite transporter
D: Formate-nitrite transporter
E: Formate-nitrite transporter
hetero molecules


Theoretical massNumber of molelcules
Total (without water)174,02210
Polymers172,4615
Non-polymers1,5615
Water362
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein
Formate-nitrite transporter


Mass: 34492.281 Da / Num. of mol.: 5
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Plasmodium falciparum (isolate 3D7) (eukaryote)
Strain: isolate 3D7 / Gene: PF3D7_0316600 / Production host: Homo sapiens (human) / References: UniProt: O77389
#2: Chemical
ChemComp-HV6 / (Z)-4,4,5,5,5-pentakis(fluoranyl)-1-(4-methoxy-2-oxidanyl-phenyl)-3-oxidanyl-pent-2-en-1-one


Mass: 312.189 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C12H9F5O4 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Formula: H2O
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: PfFNT-inhibitor complex / 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
Image recordingElectron dose: 38 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.19_4080: / Classification: refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.18 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 1044196 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00311424
ELECTRON MICROSCOPYf_angle_d0.52315507
ELECTRON MICROSCOPYf_dihedral_angle_d5.4771550
ELECTRON MICROSCOPYf_chiral_restr0.0361757
ELECTRON MICROSCOPYf_plane_restr0.0031886

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