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- EMDB-48444: Cryo-EM structure of human MPC in complex with UK5099 in nanodiscs -

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Basic information

Entry
Database: EMDB / ID: EMD-48444
TitleCryo-EM structure of human MPC in complex with UK5099 in nanodiscs
Map data
Sample
  • Complex: human MPC in nanodiscs with UK5099
    • Protein or peptide: Fab_8D3_2 heavy chain
    • Protein or peptide: Nanobody
    • Protein or peptide: Mitochondrial pyruvate carrier 2
    • Protein or peptide: Mitochondrial pyruvate carrier 1
    • Protein or peptide: MBP-PrA/G
    • Protein or peptide: Fab_8D3_2 light chain
  • Ligand: (E)-2-cyano-3-(1-phenylindol-3-yl)prop-2-enoic acid
KeywordsMembrane transporter / TRANSPORT PROTEIN-IMMUNE SYSTEM complex
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) / Mus musculus (house mouse) / synthetic construct (others) / Escherichia coli (E. coli)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.73 Å
AuthorsZhang J / He Z / Feng L
Funding support United States, 2 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS) United States
Stanford University United States
CitationJournal: Nature / Year: 2025
Title: Structure of mitochondrial pyruvate carrier and its inhibition mechanism.
Authors: Zheng He / Jianxiu Zhang / Yan Xu / Eve J Fine / Carl-Mikael Suomivuori / Ron O Dror / Liang Feng /
Abstract: The mitochondrial pyruvate carrier (MPC) governs the entry of pyruvate-a central metabolite that bridges cytosolic glycolysis with mitochondrial oxidative phosphorylation-into the mitochondrial ...The mitochondrial pyruvate carrier (MPC) governs the entry of pyruvate-a central metabolite that bridges cytosolic glycolysis with mitochondrial oxidative phosphorylation-into the mitochondrial matrix. It thus serves as a pivotal metabolic gatekeeper and has fundamental roles in cellular metabolism. Moreover, MPC is a key target for drugs aimed at managing diabetes, non-alcoholic steatohepatitis and neurodegenerative diseases. However, despite MPC's critical roles in both physiology and medicine, the molecular mechanisms underlying its transport function and how it is inhibited by drugs have remained largely unclear. Here our structural findings on human MPC define the architecture of this vital transporter, delineate its substrate-binding site and translocation pathway, and reveal its major conformational states. Furthermore, we explain the binding and inhibition mechanisms of MPC inhibitors. Our findings provide the molecular basis for understanding MPC's function and pave the way for the development of more-effective therapeutic reagents that target MPC.
History
DepositionDec 24, 2024-
Header (metadata) releaseMar 5, 2025-
Map releaseMar 5, 2025-
UpdateJun 4, 2025-
Current statusJun 4, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_48444.png

Downloads & links

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Map

FileDownload / File: emd_48444.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.)
0.86 Å/pix.
x 320 pix.
= 275.2 Å		0.86 Å/pix.
x 320 pix.
= 275.2 Å		0.86 Å/pix.
x 320 pix.
= 275.2 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.86 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.1
Minimum - Maximum-0.0017822454 - 1.9487286
Average (Standard dev.)0.0005913157 (±0.017156264)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 275.2 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: #1

Fileemd_48444_additional_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_48444_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_48444_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
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Histogram

Histogram (log scale)

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Sample components

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Entire : human MPC in nanodiscs with UK5099

EntireName: human MPC in nanodiscs with UK5099
Components
  • Complex: human MPC in nanodiscs with UK5099
    • Protein or peptide: Fab_8D3_2 heavy chain
    • Protein or peptide: Nanobody
    • Protein or peptide: Mitochondrial pyruvate carrier 2
    • Protein or peptide: Mitochondrial pyruvate carrier 1
    • Protein or peptide: MBP-PrA/G
    • Protein or peptide: Fab_8D3_2 light chain
  • Ligand: (E)-2-cyano-3-(1-phenylindol-3-yl)prop-2-enoic acid

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Supramolecule #1: human MPC in nanodiscs with UK5099

SupramoleculeName: human MPC in nanodiscs with UK5099 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#6
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Fab_8D3_2 heavy chain

MacromoleculeName: Fab_8D3_2 heavy chain / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 28.83335 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MDWTWRVFCL LAVAPGAHSD VQLVESGGGL VQPGKSLRLS CAASGFTFSN FGMHWVRQAP EMGLEWVAYI SSGSTTKYYG DTVKGRFTI SRDNPKNTLY LQMNSLRSED TAMYYCARRP LYDGDYGYPM DYWGQGTSVT VSSASTKGPS VFPLAPSSKS T SGGTAALG ...String:
MDWTWRVFCL LAVAPGAHSD VQLVESGGGL VQPGKSLRLS CAASGFTFSN FGMHWVRQAP EMGLEWVAYI SSGSTTKYYG DTVKGRFTI SRDNPKNTLY LQMNSLRSED TAMYYCARRP LYDGDYGYPM DYWGQGTSVT VSSASTKGPS VFPLAPSSKS T SGGTAALG CLVKDYFPEP VTVSWNSGAL TSGVHTFPAV LQSSGLYSLS SVVTVPSSSL GTQTYICNVN HKPSNTKVDK KV EPKSCGS LEVLFQGPHH HHHHHHHH

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Macromolecule #2: Nanobody

MacromoleculeName: Nanobody / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: synthetic construct (others)
Molecular weightTheoretical: 16.69083 KDa
Recombinant expressionOrganism: Escherichia coli BL21(DE3) (bacteria)
SequenceString:
MKYLLPTAAA GLLLLAAQPA MAQVQLQESG GGLVQAGGSL RLSCAASGTI FYYGTMGWYR QAPGKERELV ASINRGGNTN YADSVKGRF TISRDNAKNT VYLQMNSLKP EDTAVYYCAV KSGLIYAHRY WGQGTQVTVS SLEHHHHHHH HHH

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Macromolecule #3: Mitochondrial pyruvate carrier 2

MacromoleculeName: Mitochondrial pyruvate carrier 2 / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 14.298876 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
MSAAGARGLR ATYHRLLDKV ELMLPEKLRP LYNHPAGPRT VFFWAPIMKW GLVCAGLADM ARPAEKLSTA QSAVLMATGF IWSRYSLVI IPKNWSLFAV NFFVGAAGAS QLFRIWRYNQ ELKAKAHK

UniProtKB: Mitochondrial pyruvate carrier 2

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Macromolecule #4: Mitochondrial pyruvate carrier 1

MacromoleculeName: Mitochondrial pyruvate carrier 1 / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 13.094363 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
MAGALVRKAA DYVRSKDFRD YLMSTHFWGP VANWGLPIAA INDMKKSPEI ISGRMTFALC CYSLTFMRFA YKVQPRNWLL FACHATNEV AQLIQGGRLI KHEMTKTASA LEVLFQ

UniProtKB: Mitochondrial pyruvate carrier 1

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Macromolecule #5: MBP-PrA/G

MacromoleculeName: MBP-PrA/G / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Escherichia coli (E. coli)
Molecular weightTheoretical: 59.233246 KDa
Recombinant expressionOrganism: Escherichia coli BL21(DE3) (bacteria)
SequenceString: MKIEEGKLVI WINGDKGYNG LAEVGKKFEK DTGIKVTVEH PDKLEEKFPQ VAATGDGPDI IFWAHDRFGG YAQSGLLAEI TPDKAFQDK LYPFTWDAVR YNGKLIAYPI AVEALSLIYN KDLLPNPPKT WEEIPALDKE LKAKGKSALM FNLQEPYFTW P LIAADGGY ...String:
MKIEEGKLVI WINGDKGYNG LAEVGKKFEK DTGIKVTVEH PDKLEEKFPQ VAATGDGPDI IFWAHDRFGG YAQSGLLAEI TPDKAFQDK LYPFTWDAVR YNGKLIAYPI AVEALSLIYN KDLLPNPPKT WEEIPALDKE LKAKGKSALM FNLQEPYFTW P LIAADGGY AFKYENGKYD IKDVGVDNAG AKAGLTFLVD LIKNKHMNAD TDYSIAEAAF NKGETAMTIN GPWAWSNIDT SK VNYGVTV LPTFKGQPSK PFVGVLSAGI NAASPNKELA KEFLENYLLT DEGLEAVNKD KPLGAVALKS YEEELAKDPR IAA TMENAQ KGEIMPNIPQ MSAFWYAVRT AVINAASGRQ TVDQALAFAQ ILIMPNLTEE QRNGFIQSLK DDPSVSKEIL AEAK KLNEH QAPKGGSGGA GSGDQQSAFY EILNMPNLNE AQRNGFIQSL KDDPSQSTNV LGEAKKLNES QAGGGSGGGS GGSAV TTYK LVINGKTLKG ETTTKAVDAE TAEKAFKQYA NDNGVDGVWT YDDATKTFTV TEGSGHHHHH H

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Macromolecule #6: Fab_8D3_2 light chain

MacromoleculeName: Fab_8D3_2 light chain / type: protein_or_peptide / ID: 6 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 27.359672 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MVLQTQVFIS LLLWISGAYG NIMLTQSPSS LAVSAGERVT MSCKSTQSIL YNSNQKTYLA WYQQKPGQSP KLLIYWASTR ASGVPDRFT GSGSGTDFTL TINSVQPEDL AVYYCHQYLS AWTFGGGTKL EIKRTVAAPS VFIFPPSDEQ LKSGTASVVC L LNNFYPRE ...String:
MVLQTQVFIS LLLWISGAYG NIMLTQSPSS LAVSAGERVT MSCKSTQSIL YNSNQKTYLA WYQQKPGQSP KLLIYWASTR ASGVPDRFT GSGSGTDFTL TINSVQPEDL AVYYCHQYLS AWTFGGGTKL EIKRTVAAPS VFIFPPSDEQ LKSGTASVVC L LNNFYPRE AKVQWKVDNA LQSGNSQESV TEQDSKDSTY SLSSTLTLSK ADYEKHKVYA CEVTHQGLSS PVTKSFNRGE CW SHPQFEK

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Macromolecule #7: (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: 7 / 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

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 100.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.2 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: NONE
Startup modelType of model: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.73 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 570457
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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