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- EMDB-39625: Cryo-EM structure of human mitochondrial pyruvate carrier in comp... -

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Basic information

Entry
Database: EMDB / ID: EMD-39625
TitleCryo-EM structure of human mitochondrial pyruvate carrier in complex with the inhibitor UK5099
Map data
Sample
  • Complex: A membrane transporter complex
    • Protein or peptide: Mitochondrial pyruvate carrier 2
    • Protein or peptide: MPC specific nanobody 1
    • Protein or peptide: Mitochondrial pyruvate carrier 1
  • Ligand: CARDIOLIPIN
  • Ligand: (E)-2-cyano-3-(1-phenylindol-3-yl)prop-2-enoic acid
Keywordsmitochondrial pyruvate carrier / MPC / pyruvate transport / PROTEIN TRANSPORT
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 / mitochondrial inner membrane / mitochondrion / identical protein binding / nucleus
Similarity search - Function
Mitochondrial pyruvate carrier / Mitochondrial pyruvate carriers
Similarity search - Domain/homology
Mitochondrial pyruvate carrier 2 / Mitochondrial pyruvate carrier 1
Similarity search - Component
Biological speciesHomo sapiens (human) / Escherichia coli BL21(DE3) (bacteria)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.17 Å
AuthorsShi JH / Liang JM / Ma D
Funding support China, 1 items
OrganizationGrant numberCountry
Ministry of Science and Technology (MoST, China)2022YFA1303700 China
CitationJournal: Nature / Year: 2025
Title: Structures and mechanism of the human mitochondrial pyruvate carrier.
Authors: Jiaming Liang / Junhui Shi / Ailong Song / Meihua Lu / Kairan Zhang / Meng Xu / Gaoxingyu Huang / Peilong Lu / Xudong Wu / Dan Ma /
Abstract: The mitochondrial pyruvate carrier (MPC) is a mitochondrial inner membrane protein complex that is essential for the uptake of pyruvate into the mitochondrial matrix as the primary carbon source for ...The mitochondrial pyruvate carrier (MPC) is a mitochondrial inner membrane protein complex that is essential for the uptake of pyruvate into the mitochondrial matrix as the primary carbon source for the tricarboxylic acid cycle. Here we present six cryo-electron microscopy structures of human MPC in three states: three structures in the intermembrane space (IMS)-open state, obtained in different conditions; a structure of pyruvate-treated MPC in the occluded state; and two structures in the matrix-facing state, bound with the inhibitor UK5099 or with an inhibitory nanobody on the matrix side. MPC is a heterodimer consisting of MPC1 and MPC2, with the transmembrane domain adopting pseudo-C2 symmetry. Approximate rigid-body movements occur between the IMS-open state and the occluded state, whereas structural changes, mainly on the matrix side, facilitate the transition between the occluded state and the matrix-facing state, revealing an alternating access mechanism during pyruvate transport. In the UK5099-bound structure, the inhibitor fits well and interacts extensively with a pocket that opens to the matrix side. Our findings provide key insights into the mechanisms that underlie MPC-mediated substrate transport, and shed light on the recognition and inhibition of MPC by UK5099, which will facilitate the future development of drugs that target MPC.
History
DepositionMar 30, 2024-
Header (metadata) releaseMar 12, 2025-
Map releaseMar 12, 2025-
UpdateApr 2, 2025-
Current statusApr 2, 2025Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_39625.png

Downloads & links

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Map

FileDownload / File: emd_39625.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.57 Å/pix.
x 320 pix.
= 182.4 Å		0.57 Å/pix.
x 320 pix.
= 182.4 Å		0.57 Å/pix.
x 320 pix.
= 182.4 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.57 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.09
Minimum - Maximum-0.55860394 - 0.79833
Average (Standard dev.)0.00060991297 (±0.014770303)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 182.4 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_39625_half_map_1.map
Projections & Slices
AxesZYX

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Density Histograms

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Histogram (log scale)

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Half map: #1

Fileemd_39625_half_map_2.map
Projections & Slices
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Sample components

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Entire : A membrane transporter complex

EntireName: A membrane transporter complex
Components
  • Complex: A membrane transporter complex
    • Protein or peptide: Mitochondrial pyruvate carrier 2
    • Protein or peptide: MPC specific nanobody 1
    • Protein or peptide: Mitochondrial pyruvate carrier 1
  • Ligand: CARDIOLIPIN
  • Ligand: (E)-2-cyano-3-(1-phenylindol-3-yl)prop-2-enoic acid

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Supramolecule #1: A membrane transporter complex

SupramoleculeName: A membrane transporter complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Mitochondrial pyruvate carrier 2

MacromoleculeName: Mitochondrial pyruvate carrier 2 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 17.161725 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
MSAAGARGLR ATYHRLLDKV ELMLPEKLRP LYNHPAGPRT VFFWAPIMKW GLVCAGLADM ARPAEKLSTA QSAVLMATGF IWSRYSLVI IPKNWSLFAV NFFVGAAGAS QLFRIWRYNQ ELKAKAHKGS DYKDHDGDYK DHDIDYKDDD DK

UniProtKB: Mitochondrial pyruvate carrier 2

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Macromolecule #2: MPC specific nanobody 1

MacromoleculeName: MPC specific nanobody 1 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Escherichia coli BL21(DE3) (bacteria)
Molecular weightTheoretical: 15.25583 KDa
Recombinant expressionOrganism: Escherichia coli BL21(DE3) (bacteria)
SequenceString:
EVQLVESGGG LVQAGGSLRL SCAASGFPVT ERVMYWYRQA PGKEREWVAA IDSQGSSTYY ADSVKGRFTI SRDNSKNTVY LQMNSLKPE DTAVYYCKVE VGWGYKGQGT QVTVSSLEHH HHHHHGGSGE QKLISEEDL

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Macromolecule #3: Mitochondrial pyruvate carrier 1

MacromoleculeName: Mitochondrial pyruvate carrier 1 / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 13.592766 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
MAGALVRKAA DYVRSKDFRD YLMSTHFWGP VANWGLPIAA INDMKKSPEI ISGRMTFALC CYSLTFMRFA YKVQPRNWLL FACHATNEV AQLIQGGRLI KHEMTKTASA GSYPYDVPDY A

UniProtKB: Mitochondrial pyruvate carrier 1

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Macromolecule #4: CARDIOLIPIN

MacromoleculeName: CARDIOLIPIN / type: ligand / ID: 4 / Number of copies: 1 / Formula: CDL
Molecular weightTheoretical: 1.464043 KDa
Chemical component information

ChemComp-CDL:
CARDIOLIPIN / phospholipid*YM

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Macromolecule #5: (E)-2-cyano-3-(1-phenylindol-3-yl)prop-2-enoic acid

MacromoleculeName: (E)-2-cyano-3-(1-phenylindol-3-yl)prop-2-enoic acid / type: ligand / ID: 5 / Number of copies: 1 / Formula: I2R
Molecular weightTheoretical: 288.3 Da
Chemical component information

ChemComp-I2R:
(E)-2-cyano-3-(1-phenylindol-3-yl)prop-2-enoic acid

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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: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.2 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.17 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 697227
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: MAXIMUM LIKELIHOOD / Details: AF2 predicted

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