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- EMDB-35928: Structure of human UCP1 in the DNP-bound state -

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Basic information

Entry
Database: EMDB / ID: EMD-35928
TitleStructure of human UCP1 in the DNP-bound state
Map dataSharpened map
Sample
  • Complex: UCP1-sybody complex
    • Protein or peptide: Mitochondrial brown fat uncoupling protein 1
    • Protein or peptide: Sybody 12F2
  • Ligand: 2,4-DINITROPHENOL
  • Ligand: CARDIOLIPIN
  • Ligand: 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE
KeywordsUCP1 / SLC25A7 / thermogenin / SLC25 / MEMBRANE PROTEIN
Function / homology
Function and homology information


purine ribonucleotide binding / cellular response to dehydroepiandrosterone / The fatty acid cycling model / : / oxidative phosphorylation uncoupler activity / mitochondrial transmembrane transport / adaptive thermogenesis / cardiolipin binding / regulation of reactive oxygen species biosynthetic process / cellular response to cold ...purine ribonucleotide binding / cellular response to dehydroepiandrosterone / The fatty acid cycling model / : / oxidative phosphorylation uncoupler activity / mitochondrial transmembrane transport / adaptive thermogenesis / cardiolipin binding / regulation of reactive oxygen species biosynthetic process / cellular response to cold / cellular response to fatty acid / response to temperature stimulus / long-chain fatty acid binding / diet induced thermogenesis / proton transmembrane transporter activity / transmembrane transporter activity / brown fat cell differentiation / cellular response to hormone stimulus / proton transmembrane transport / response to cold / response to nutrient levels / cellular response to reactive oxygen species / GDP binding / positive regulation of cold-induced thermogenesis / mitochondrial inner membrane / GTP binding / regulation of transcription by RNA polymerase II / mitochondrion
Similarity search - Function
Mitochondrial carrier protein / Mitochondrial substrate/solute carrier / Mitochondrial carrier domain superfamily / Mitochondrial carrier protein / Solute carrier (Solcar) repeat profile.
Similarity search - Domain/homology
Mitochondrial brown fat uncoupling protein 1
Similarity search - Component
Biological speciesHomo sapiens (human) / synthetic construct (others)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.51 Å
AuthorsChen L / Kang Y
Funding support China, 5 items
OrganizationGrant numberCountry
Ministry of Science and Technology (MoST, China)2106YFA0502004 China
National Natural Science Foundation of China (NSFC)31622021 China
National Natural Science Foundation of China (NSFC)31821091 China
National Natural Science Foundation of China (NSFC)31870833 China
National Natural Science Foundation of China (NSFC)8200907150 China
CitationJournal: Nature / Year: 2023
Title: Structural basis for the binding of DNP and purine nucleotides onto UCP1.
Authors: Yunlu Kang / Lei Chen /
Abstract: Uncoupling protein 1 (UCP1) conducts protons through the inner mitochondrial membrane to uncouple mitochondrial respiration from ATP production, thereby converting the electrochemical gradient of ...Uncoupling protein 1 (UCP1) conducts protons through the inner mitochondrial membrane to uncouple mitochondrial respiration from ATP production, thereby converting the electrochemical gradient of protons into heat. The activity of UCP1 is activated by endogenous fatty acids and synthetic small molecules, such as 2,4-dinitrophenol (DNP), and is inhibited by purine nucleotides, such as ATP. However, the mechanism by which UCP1 binds to these ligands remains unknown. Here we present the structures of human UCP1 in the nucleotide-free state, the DNP-bound state and the ATP-bound state. The structures show that the central cavity of UCP1 is open to the cytosolic side. DNP binds inside the cavity, making contact with transmembrane helix 2 (TM2) and TM6. ATP binds in the same cavity and induces conformational changes in TM2, together with the inward bending of TM1, TM4, TM5 and TM6 of UCP1, resulting in a more compact structure of UCP1. The binding site of ATP overlaps with that of DNP, suggesting that ATP competitively blocks the functional engagement of DNP, resulting in the inhibition of the proton-conducting activity of UCP1.
History
DepositionApr 13, 2023-
Header (metadata) releaseJun 21, 2023-
Map releaseJun 21, 2023-
UpdateAug 30, 2023-
Current statusAug 30, 2023Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_35928.png

Downloads & links

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Map

FileDownload / File: emd_35928.map.gz / Format: CCP4 / Size: 83.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationSharpened map
Voxel sizeX=Y=Z: 0.834 Å
Density
Contour LevelBy AUTHOR: 0.904
Minimum - Maximum-6.2610598 - 12.010852
Average (Standard dev.)-0.0006540669 (±0.14588468)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions280280280
Spacing280280280
CellA=B=C: 233.52 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Half map A

Fileemd_35928_half_map_1.map
AnnotationHalf map A
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map B

Fileemd_35928_half_map_2.map
AnnotationHalf map B
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : UCP1-sybody complex

EntireName: UCP1-sybody complex
Components
  • Complex: UCP1-sybody complex
    • Protein or peptide: Mitochondrial brown fat uncoupling protein 1
    • Protein or peptide: Sybody 12F2
  • Ligand: 2,4-DINITROPHENOL
  • Ligand: CARDIOLIPIN
  • Ligand: 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE

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Supramolecule #1: UCP1-sybody complex

SupramoleculeName: UCP1-sybody complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Mitochondrial brown fat uncoupling protein 1

MacromoleculeName: Mitochondrial brown fat uncoupling protein 1 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 39.468367 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MSRLEEELRR RLTEGSGGWS HPQFEKGSGD YKDDDDKGSG WSHPQFEKLE VLFQGPMGGL TASDVHPTLG VQLFSAGIAA CLADVITFP LDTAKVRLQV QGECPTSSVI RYKGVLGTIT AVVKTEGRMK LYSGLPAGLQ RQISSASLRI GLYDTVQEFL T AGKETAPS ...String:
MSRLEEELRR RLTEGSGGWS HPQFEKGSGD YKDDDDKGSG WSHPQFEKLE VLFQGPMGGL TASDVHPTLG VQLFSAGIAA CLADVITFP LDTAKVRLQV QGECPTSSVI RYKGVLGTIT AVVKTEGRMK LYSGLPAGLQ RQISSASLRI GLYDTVQEFL T AGKETAPS LGSKILAGLT TGGVAVFIGQ PTEVVKVRLQ AQSHLHGIKP RYTGTYNAYR IIATTEGLTG LWKGTTPNLM RS VIINCTE LVTYDLMKEA FVKNNILADD VPCHLVSALI AGFCATAMSS PVDVVKTRFI NSPPGQYKSV PNCAMKVFTN EGP TAFFKG LVPSFLRLGS WNVIMFVCFE QLKRELSKSR QTMDCAT

UniProtKB: Mitochondrial brown fat uncoupling protein 1

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Macromolecule #2: Sybody 12F2

MacromoleculeName: Sybody 12F2 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: synthetic construct (others)
Molecular weightTheoretical: 15.004661 KDa
SequenceString:
MGQVQLVESG GGLVQAGGSL RLSCAASGFP VMYYNMHWYR QAPGKEREWV AAIESTGWWA HYADSVKGRF TISRDNAKNT VYLQMNSLK PEDTAVYYCN VKDFGWRWEA YDYWGQGTQV TVSSLEHHHH HH

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Macromolecule #3: 2,4-DINITROPHENOL

MacromoleculeName: 2,4-DINITROPHENOL / type: ligand / ID: 3 / Number of copies: 1 / Formula: DNF
Molecular weightTheoretical: 184.106 Da
Chemical component information

ChemComp-DNF:
2,4-DINITROPHENOL

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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: 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE

MacromoleculeName: 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE / type: ligand / ID: 5 / Number of copies: 2 / Formula: PC1
Molecular weightTheoretical: 790.145 Da
Chemical component information

ChemComp-PC1:
1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE / phospholipid*YM

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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: 8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 52.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.8 µm / Nominal defocus min: 1.5 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.51 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 709625
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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