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- EMDB-51381: Structure of the human mitochondrial pyruvate carrier inhibited b... -

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Basic information

Entry
Database: EMDB / ID: EMD-51381
TitleStructure of the human mitochondrial pyruvate carrier inhibited by mitoglitazone
Map dataMap used for model building and refinement
Sample
  • Complex: Complex of human mitochondrial pyruvate carrier (MPC1L/MPC2) inhibited by mitoglitazone with a pro-macrobody
    • Complex: Mitochondrial pyruvate carrier (MPC1L/MPC2)
      • Protein or peptide: Mitochondrial pyruvate carrier 1-like protein
      • Protein or peptide: Mitochondrial pyruvate carrier 2
    • Complex: Macrobody with C-terminal MBP tag
      • Protein or peptide: Macrobody,Maltose/maltodextrin-binding periplasmic protein
  • Ligand: Mitoglitazone
  • Ligand: Mitoglitazone (R-form)
Keywordstransporter SLC54 pyruvate UK5099-derivative / MEMBRANE PROTEIN
Function / homology
Function and homology information


pyruvate import into mitochondria / inner mitochondrial membrane protein complex / pyruvate transmembrane transporter activity / pyruvate decarboxylation to acetyl-CoA / Pyruvate metabolism / positive regulation of insulin secretion involved in cellular response to glucose stimulus / carbohydrate transmembrane transporter activity / maltose binding / maltose transport / maltodextrin transmembrane transport ...pyruvate import into mitochondria / inner mitochondrial membrane protein complex / pyruvate transmembrane transporter activity / pyruvate decarboxylation to acetyl-CoA / Pyruvate metabolism / positive regulation of insulin secretion involved in cellular response to glucose stimulus / carbohydrate transmembrane transporter activity / maltose binding / maltose transport / maltodextrin transmembrane transport / ATP-binding cassette (ABC) transporter complex, substrate-binding subunit-containing / outer membrane-bounded periplasmic space / mitochondrial inner membrane / mitochondrion / identical protein binding / nucleus
Similarity search - Function
Mitochondrial pyruvate carrier / Mitochondrial pyruvate carriers / Maltose/Cyclodextrin ABC transporter, substrate-binding protein / Solute-binding family 1, conserved site / Bacterial extracellular solute-binding proteins, family 1 signature. / Bacterial extracellular solute-binding protein / Bacterial extracellular solute-binding protein
Similarity search - Domain/homology
Mitochondrial pyruvate carrier 2 / Maltose/maltodextrin-binding periplasmic protein / Mitochondrial pyruvate carrier 1-like protein
Similarity search - Component
Biological speciesHomo sapiens (human) / synthetic construct (others) / Escherichia coli K-12 (bacteria)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.79 Å
AuthorsSichrovsky M / Lacabanne D / Ruprecht JJ / Rana JJ / Stanik K / Dionysopoulou M / King MS / Sowton AP / Jones S / Cooper L ...Sichrovsky M / Lacabanne D / Ruprecht JJ / Rana JJ / Stanik K / Dionysopoulou M / King MS / Sowton AP / Jones S / Cooper L / Hardwick SW / Paris G / Chirgadze DY / Ding S / Fearnley IM / Palmer S / Pardon E / Steyaert J / Leone V / Forrest LR / Tavoulari S / Kunji ERS
Funding support United Kingdom, European Union, Belgium, United States, 4 items
OrganizationGrant numberCountry
Medical Research Council (MRC, United Kingdom)MC_UU_00028/2 United Kingdom
European Union (EU)Instruct-ERIC part of the European Strategy Forum on Research infrastructures (ESFRI) (PID: 22183)European Union
Research Foundation - Flanders (FWO) Belgium
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)NS003139 United States
CitationJournal: Sci Adv / Year: 2025
Title: Molecular basis of pyruvate transport and inhibition of the human mitochondrial pyruvate carrier.
Authors: Maximilian Sichrovsky / Denis Lacabanne / Jonathan J Ruprecht / Jessica J Rana / Klaudia Stanik / Mariangela Dionysopoulou / Alice P Sowton / Martin S King / Scott A Jones / Lee Cooper / ...Authors: Maximilian Sichrovsky / Denis Lacabanne / Jonathan J Ruprecht / Jessica J Rana / Klaudia Stanik / Mariangela Dionysopoulou / Alice P Sowton / Martin S King / Scott A Jones / Lee Cooper / Steven W Hardwick / Giulia Paris / Dimitri Y Chirgadze / Shujing Ding / Ian M Fearnley / Shane M Palmer / Els Pardon / Jan Steyaert / Vanessa Leone / Lucy R Forrest / Sotiria Tavoulari / Edmund R S Kunji /
Abstract: The mitochondrial pyruvate carrier transports pyruvate, produced by glycolysis from sugar molecules, into the mitochondrial matrix, as a crucial transport step in eukaryotic energy metabolism. The ...The mitochondrial pyruvate carrier transports pyruvate, produced by glycolysis from sugar molecules, into the mitochondrial matrix, as a crucial transport step in eukaryotic energy metabolism. The carrier is a drug target for the treatment of cancers, diabetes mellitus, neurodegeneration, and metabolic dysfunction-associated steatotic liver disease. We have solved the structure of the human MPC1L/MPC2 heterodimer in the inward- and outward-open states by cryo-electron microscopy, revealing its alternating access rocker-switch mechanism. The carrier has a central binding site for pyruvate, which contains an essential lysine and histidine residue, important for its ΔpH-dependent transport mechanism. We have also determined the binding poses of three chemically distinct inhibitor classes, which exploit the same binding site in the outward-open state by mimicking pyruvate interactions and by using aromatic stacking interactions.
History
DepositionAug 19, 2024-
Header (metadata) releaseMay 7, 2025-
Map releaseMay 7, 2025-
UpdateMay 7, 2025-
Current statusMay 7, 2025Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_51381.png

Downloads & links

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Map

FileDownload / File: emd_51381.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationMap used for model building and refinement
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.18 Å/pix.
x 256 pix.
= 303.264 Å		1.18 Å/pix.
x 256 pix.
= 303.264 Å		1.18 Å/pix.
x 256 pix.
= 303.264 Å

Surface

Projections

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Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.18463 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.4
Minimum - Maximum-1.8365076 - 3.1628098
Average (Standard dev.)0.00076432474 (±0.03207721)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 303.264 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_51381_msk_1.map
Projections & Slices
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Histogram (log scale)

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Additional map: Map from non-uniform refinement, used for model building

Fileemd_51381_additional_1.map
AnnotationMap from non-uniform refinement, used for model building
Projections & Slices
AxesZYX

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Half map: #2

Fileemd_51381_half_map_1.map
Projections & Slices
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Histogram

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Half map: #1

Fileemd_51381_half_map_2.map
Projections & Slices
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Sample components

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Entire : Complex of human mitochondrial pyruvate carrier (MPC1L/MPC2) inhi...

EntireName: Complex of human mitochondrial pyruvate carrier (MPC1L/MPC2) inhibited by mitoglitazone with a pro-macrobody
Components
  • Complex: Complex of human mitochondrial pyruvate carrier (MPC1L/MPC2) inhibited by mitoglitazone with a pro-macrobody
    • Complex: Mitochondrial pyruvate carrier (MPC1L/MPC2)
      • Protein or peptide: Mitochondrial pyruvate carrier 1-like protein
      • Protein or peptide: Mitochondrial pyruvate carrier 2
    • Complex: Macrobody with C-terminal MBP tag
      • Protein or peptide: Macrobody,Maltose/maltodextrin-binding periplasmic protein
  • Ligand: Mitoglitazone
  • Ligand: Mitoglitazone (R-form)

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Supramolecule #1: Complex of human mitochondrial pyruvate carrier (MPC1L/MPC2) inhi...

SupramoleculeName: Complex of human mitochondrial pyruvate carrier (MPC1L/MPC2) inhibited by mitoglitazone with a pro-macrobody
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3

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Supramolecule #2: Mitochondrial pyruvate carrier (MPC1L/MPC2)

SupramoleculeName: Mitochondrial pyruvate carrier (MPC1L/MPC2) / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #3: Macrobody with C-terminal MBP tag

SupramoleculeName: Macrobody with C-terminal MBP tag / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #3
Source (natural)Organism: synthetic construct (others)

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Macromolecule #1: Mitochondrial pyruvate carrier 1-like protein

MacromoleculeName: Mitochondrial pyruvate carrier 1-like protein / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 15.155544 KDa
Recombinant expressionOrganism: Saccharomyces cerevisiae (brewer's yeast)
SequenceString:
MARMAVLWRK MRDNFQSKEF REYVSSTHFW GPAFSWGLPL AAFKDMKASP EIISGRMTTA LILYSAIFMR FAYRVQPRNL LLMACHCTN VMAQSVQASR YLLYYYGGGG AEAKARDPPA TAAAATSPGS QPPKQAS

UniProtKB: Mitochondrial pyruvate carrier 1-like protein

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Macromolecule #2: Mitochondrial pyruvate carrier 2

MacromoleculeName: Mitochondrial pyruvate carrier 2 / type: protein_or_peptide / ID: 2
Details: MPC2 expressed with a TEV-cleavable His tag. Sequence is of purified protein post-TEV cleavage
Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 15.093728 KDa
Recombinant expressionOrganism: Saccharomyces cerevisiae (brewer's yeast)
SequenceString:
MSAAGARGLR ATYHRLLDKV ELMLPEKLRP LYNHPAGPRT VFFWAPIMKW GLVCAGLADM ARPAEKLSTA QSAVLMATGF IWSRYSLVI IPKNWSLFAV NFFVGAAGAS QLFRIWRYNQ ELKAKAHKEN LYFQ

UniProtKB: Mitochondrial pyruvate carrier 2

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Macromolecule #3: Macrobody,Maltose/maltodextrin-binding periplasmic protein

MacromoleculeName: Macrobody,Maltose/maltodextrin-binding periplasmic protein
type: protein_or_peptide / ID: 3
Details: Pro-macrobody is a MBP-nanobody-MBP fusion protein with a 3C protease-cleavable tag between the N-terminal MBP and nanobody. Sequence shows final purified protein post cleavage.,Pro- ...Details: Pro-macrobody is a MBP-nanobody-MBP fusion protein with a 3C protease-cleavable tag between the N-terminal MBP and nanobody. Sequence shows final purified protein post cleavage.,Pro-macrobody is a MBP-nanobody-MBP fusion protein with a 3C protease-cleavable tag between the N-terminal MBP and nanobody. Sequence shows final purified protein post cleavage.
Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Escherichia coli K-12 (bacteria)
Molecular weightTheoretical: 56.307047 KDa
Recombinant expressionOrganism: Escherichia coli MC1061 (bacteria)
SequenceString: GPSQVQLVES GGGLVQAGGS LRLSCAASGR TFSAYGISTY TMGWFRQAPG KEREFVAAIG RDSGFTYYED SVKGRFTINA DNAENTVYL QMNSLKPEDT AVYYCAASSY YGRPNVDLMA YWGKGTQVTV PPLVIWINGD KGYNGLAEVG KKFEKDTGIK V TVEHPDKL ...String:
GPSQVQLVES GGGLVQAGGS LRLSCAASGR TFSAYGISTY TMGWFRQAPG KEREFVAAIG RDSGFTYYED SVKGRFTINA DNAENTVYL QMNSLKPEDT AVYYCAASSY YGRPNVDLMA YWGKGTQVTV PPLVIWINGD KGYNGLAEVG KKFEKDTGIK V TVEHPDKL EEKFPQVAAT GDGPDIIFWA HDRFGGYAQS GLLAEITPDK AFQDKLYPFT WDAVRYNGKL IAYPIAVEAL SL IYNKDLL PNPPKTWEEI PALDKELKAK GKSALMFNLQ EPYFTWPLIA ADGGYAFKYE NGKYDIKDVG VDNAGAKAGL TFL VDLIKN KHMNADTDYS IAEAAFNKGE TAMTINGPWA WSNIDTSKVN YGVTVLPTFK GQPSKPFVGV LSAGINAASP NKEL AKEFL ENYLLTDEGL EAVNKDKPLG AVALKSYEEE LAKDPRIAAT MENAQKGEIM PNIPQMSAFW YAVRTAVINA ASGRQ TVDE ALKDAQTPGS PDAAIEGRTS EDAWSHPQFE K

UniProtKB: Maltose/maltodextrin-binding periplasmic protein

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Macromolecule #4: Mitoglitazone

MacromoleculeName: Mitoglitazone / type: ligand / ID: 4 / Number of copies: 1 / Formula: LO7
Molecular weightTheoretical: 370.422 Da
Chemical component information

ChemComp-LO7:
Mitoglitazone

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Macromolecule #5: Mitoglitazone (R-form)

MacromoleculeName: Mitoglitazone (R-form) / type: ligand / ID: 5 / Number of copies: 1 / Formula: A1IMZ
Molecular weightTheoretical: 370.422 Da

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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
Component:
ConcentrationNameFormula
20.0 mMBis-Tris pH7.0
150.0 mMSodium chlorideNaCl
0.1 mg/mlTetraoleoyl cardiolipin
0.1 %LMNG detergent
2.0 mMD-maltose
0.035 %Fluorinated octyl maltoside
250.0 uMMitoglitazone
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 30 sec. / Details: 10 mA current
VitrificationCryogen name: ETHANE / Chamber humidity: 95 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Specialist opticsEnergy filter - Name: TFS Selectris X / Energy filter - Slit width: 10 eV
Image recordingFilm or detector model: TFS FALCON 4i (4k x 4k) / Number grids imaged: 1 / Average exposure time: 4.39 sec. / Average electron dose: 53.69 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 50.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.8 µm / Nominal defocus min: 0.6 µm / Nominal magnification: 165000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 1555900
CTF correctionSoftware - Name: Warp / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final reconstructionNumber classes used: 1 / Applied symmetry - Point group: C1 (asymmetric) / Algorithm: FOURIER SPACE / Resolution.type: BY AUTHOR / Resolution: 3.79 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 3.3.2) / Number images used: 190059
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 3.3.2) / Details: ab-initio reconstruction in cryosparc
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 3.3.2)
Final 3D classificationNumber classes: 5 / Software - Name: cryoSPARC (ver. 3.3.2)
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelChain - Source name: Other / Chain - Initial model type: experimental model
Details: D_1292140991 (recently deposited at PDB) was initial model
RefinementSpace: REAL / Protocol: FLEXIBLE FIT / Target criteria: Cross-correlation coefficient
Output model

PDB-9giy:
Structure of the human mitochondrial pyruvate carrier inhibited by mitoglitazone

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