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- PDB-9mnx: Cryo-EM structure of human MPC in complex with UK5099 in LMNG -

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Basic information

Entry
Database: PDB / ID: 9mnx
TitleCryo-EM structure of human MPC in complex with UK5099 in LMNG
Components
  • (Mitochondrial pyruvate carrier ...) x 2
  • Fab_8D3_2 heavy chain
  • Fab_8D3_2 light chain
  • MBP-PrA/G
  • Nanobody
KeywordsTRANSPORT PROTEIN/IMMUNE SYSTEM / Membrane 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
Chem-I2R / 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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.11 Å
AuthorsZhang, J. / He, Z. / Feng, L.
Funding support United States, 2items
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, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 5, 2025Provider: repository / Type: Initial release
Revision 1.0Mar 5, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Mar 5, 2025Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Mar 5, 2025Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Mar 5, 2025Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Mar 5, 2025Data content type: Mask / Part number: 1 / Data content type: Mask / Provider: repository / Type: Initial release
Revision 1.0Mar 5, 2025Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Mar 19, 2025Group: Data collection / Database references / Category: citation / em_admin
Item: _citation.pdbx_database_id_PubMed / _citation.title / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
B: Mitochondrial pyruvate carrier 2
A: Mitochondrial pyruvate carrier 1
D: Fab_8D3_2 heavy chain
E: Fab_8D3_2 light chain
C: Nanobody
F: MBP-PrA/G
hetero molecules


Theoretical massNumber of molelcules
Total (without water)159,7997
Polymers159,5106
Non-polymers2881
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Mitochondrial pyruvate carrier ... , 2 types, 2 molecules BA

#1: Protein Mitochondrial pyruvate carrier 2 / Brain protein 44


Mass: 14298.876 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MPC2, BRP44 / Production host: Homo sapiens (human) / References: UniProt: O95563
#2: Protein Mitochondrial pyruvate carrier 1 / Brain protein 44-like protein


Mass: 13094.363 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MPC1, BRP44L, CGI-129, HSPC040, PNAS-115 / Production host: Homo sapiens (human) / References: UniProt: Q9Y5U8

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Antibody , 3 types, 3 molecules DEC

#3: Antibody Fab_8D3_2 heavy chain


Mass: 28833.350 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Homo sapiens (human)
#4: Antibody Fab_8D3_2 light chain


Mass: 27359.672 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Homo sapiens (human)
#5: Antibody Nanobody


Mass: 16690.830 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) synthetic construct (others) / Production host: Escherichia coli BL21(DE3) (bacteria)

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Protein / Non-polymers , 2 types, 2 molecules F

#6: Protein MBP-PrA/G


Mass: 59233.246 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Escherichia coli (E. coli) / Production host: Escherichia coli BL21(DE3) (bacteria)
#7: Chemical ChemComp-I2R / (E)-2-cyano-3-(1-phenylindol-3-yl)prop-2-enoic acid / UK-5099


Mass: 288.300 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H12N2O2 / Feature type: SUBJECT OF INVESTIGATION

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Details

Has ligand of interestY
Has protein modificationY

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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: human MPC in LMNG with UK5099 / Type: COMPLEX / Entity ID: #1-#6 / Source: MULTIPLE SOURCES
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.4
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: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 1200 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

CTF correctionType: NONE
3D reconstructionResolution: 3.11 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 504636 / Symmetry type: POINT
RefinementHighest resolution: 3.11 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0215414
ELECTRON MICROSCOPYf_angle_d1.3677333
ELECTRON MICROSCOPYf_dihedral_angle_d7.596738
ELECTRON MICROSCOPYf_chiral_restr0.085782
ELECTRON MICROSCOPYf_plane_restr0.011938

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