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- PDB-8yw9: Cryo-EM structure of human mitochondrial pyruvate carrier in the ... -

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Basic information

Entry
Database: PDB / ID: 8yw9
TitleCryo-EM structure of human mitochondrial pyruvate carrier in the matrix-facing conformation at pH 6.8
Components
  • MPC specific nanobody 1
  • MPC specific nanobody 2
  • Mitochondrial pyruvate carrier 1
  • Mitochondrial pyruvate carrier 2
KeywordsPROTEIN TRANSPORT / mitochondrial pyruvate carrier / MPC / pyruvate 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
CARDIOLIPIN / Mitochondrial pyruvate carrier 2 / Mitochondrial pyruvate carrier 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Escherichia coli BL21 (bacteria)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.01 Å
AuthorsShi, J.H. / Liang, J.M. / Ma, D.
Funding support China, 1items
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, 2024Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Mar 12, 2025Provider: repository / Type: Initial release
Revision 1.0Mar 12, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Mar 12, 2025Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Mar 12, 2025Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Mar 12, 2025Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Mar 12, 2025Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Apr 2, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
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Revision 1.2May 14, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
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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
C: MPC specific nanobody 2
D: MPC specific nanobody 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)61,6895
Polymers60,2254
Non-polymers1,4641
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

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


Mass: 17161.725 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: 13592.766 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
#3: Antibody MPC specific nanobody 2


Mass: 14214.690 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Escherichia coli BL21(DE3) (bacteria) / Production host: Escherichia coli BL21(DE3) (bacteria)
#4: Antibody MPC specific nanobody 1


Mass: 15255.830 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Escherichia coli BL21(DE3) (bacteria) / Production host: Escherichia coli BL21(DE3) (bacteria)
#5: Chemical ChemComp-CDL / CARDIOLIPIN / DIPHOSPHATIDYL GLYCEROL / BIS-(1,2-DIACYL-SN-GLYCERO-3-PHOSPHO)-1',3'-SN-GLYCEROL


Mass: 1464.043 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C81H156O17P2 / Comment: phospholipid*YM
Has ligand of interestN
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: A membrane transporter complex / Type: COMPLEX / Entity ID: #1-#3 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 6.8
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: 1200 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

EM softwareName: PHENIX / Version: 1.17.1_3660: / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.01 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 1023013 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0053729
ELECTRON MICROSCOPYf_angle_d0.5225050
ELECTRON MICROSCOPYf_dihedral_angle_d5.298515
ELECTRON MICROSCOPYf_chiral_restr0.041525
ELECTRON MICROSCOPYf_plane_restr0.004642

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