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- EMDB-50894: Proton conductance by human uncoupling protein 1 is inhibited by ... -

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Basic information

Entry
Database: EMDB / ID: EMD-50894
TitleProton conductance by human uncoupling protein 1 is inhibited by both purine and pyrimidine nucleotides
Map data
Sample
  • Complex: UCP1 bound to UTP and in complex with two Pro-macrobodies
    • Protein or peptide: Mitochondrial brown fat uncoupling protein 1
    • Protein or peptide: CA9871
    • Protein or peptide: CA9865
  • Ligand: URIDINE 5'-TRIPHOSPHATE
  • Ligand: CARDIOLIPIN
KeywordsTRANSPORT PROTEIN
Function / homology
Function and homology information


purine ribonucleotide binding / cellular response to dehydroepiandrosterone / Mitochondrial Uncoupling / 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 fatty acid ...purine ribonucleotide binding / cellular response to dehydroepiandrosterone / Mitochondrial Uncoupling / 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 fatty acid / response to temperature stimulus / long-chain fatty acid binding / cellular response to cold / diet induced thermogenesis / proton transmembrane transporter activity / transmembrane transporter activity / brown fat cell differentiation / Transcriptional regulation of brown and beige adipocyte differentiation by EBF2 / cellular response to hormone stimulus / proton transmembrane transport / response to cold / cellular response to reactive oxygen species / response to nutrient levels / GDP binding / positive regulation of cold-induced thermogenesis / mitochondrial inner membrane / regulation of transcription by RNA polymerase II / GTP binding / 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) / Lama glama (llama)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.03 Å
AuthorsJones SA / Sowton AP / Lacabanne D / King MS / Palmer SM / Zogg T / Pardon E / Steyaert J / Ruprecht JJ / Kunji ERS
Funding support United Kingdom, European Union, Belgium, 3 items
OrganizationGrant numberCountry
Medical Research Council (MRC, United Kingdom)MC_UU_00028/2 United Kingdom
European Union (EU)Instruct-ERIC/ESFRIEuropean Union
Research Foundation - Flanders (FWO) Belgium
CitationJournal: EMBO J / Year: 2025
Title: Proton conductance by human uncoupling protein 1 is inhibited by purine and pyrimidine nucleotides.
Authors: Scott A Jones / Alice P Sowton / Denis Lacabanne / Martin S King / Shane M Palmer / Thomas Zögg / Els Pardon / Jan Steyaert / Jonathan J Ruprecht / Edmund R S Kunji /
Abstract: Uncoupling protein 1 (UCP1, SLC25A7) is responsible for the thermogenic properties of brown adipose tissue. Upon fatty acid activation, UCP1 facilitates proton leakage, dissipating the mitochondrial ...Uncoupling protein 1 (UCP1, SLC25A7) is responsible for the thermogenic properties of brown adipose tissue. Upon fatty acid activation, UCP1 facilitates proton leakage, dissipating the mitochondrial proton motive force to release energy as heat. Purine nucleotides are considered to be the only inhibitors of UCP1 activity, binding to its central cavity to lock UCP1 in a proton-impermeable conformation. Here we show that pyrimidine nucleotides can also bind and inhibit its proton-conducting activity. All nucleotides bound in a pH-dependent manner, with the highest binding affinity observed for ATP, followed by dTTP, UTP, GTP and CTP. We also determined the structural basis of UTP binding to UCP1, showing that binding of purine and pyrimidine nucleotides follows the same molecular principles. We find that the closely related mitochondrial dicarboxylate carrier (SLC25A10) and oxoglutarate carrier (SLC25A11) have many cavity residues in common, but do not bind nucleotides. Thus, while UCP1 has evolved from dicarboxylate carriers, no selection for nucleobase specificity has occurred, highlighting the importance of the pH-dependent nucleotide binding mechanism mediated via the phosphate moieties.
History
DepositionJul 5, 2024-
Header (metadata) releaseMar 5, 2025-
Map releaseMar 5, 2025-
UpdateApr 30, 2025-
Current statusApr 30, 2025Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_50894.png

Downloads & links

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Map

FileDownload / File: emd_50894.map.gz / Format: CCP4 / Size: 512 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.65 Å/pix.
x 512 pix.
= 330.24 Å		0.65 Å/pix.
x 512 pix.
= 330.24 Å		0.65 Å/pix.
x 512 pix.
= 330.24 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.645 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.1
Minimum - Maximum-0.6927433 - 0.8379715
Average (Standard dev.)-0.000052878266 (±0.007173175)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions512512512
Spacing512512512
CellA=B=C: 330.24 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_50894_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_50894_half_map_2.map
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 bound to UTP and in complex with two Pro-macrobodies

EntireName: UCP1 bound to UTP and in complex with two Pro-macrobodies
Components
  • Complex: UCP1 bound to UTP and in complex with two Pro-macrobodies
    • Protein or peptide: Mitochondrial brown fat uncoupling protein 1
    • Protein or peptide: CA9871
    • Protein or peptide: CA9865
  • Ligand: URIDINE 5'-TRIPHOSPHATE
  • Ligand: CARDIOLIPIN

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Supramolecule #1: UCP1 bound to UTP and in complex with two Pro-macrobodies

SupramoleculeName: UCP1 bound to UTP and in complex with two Pro-macrobodies
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
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: 33.339629 KDa
Recombinant expressionOrganism: Saccharomyces cerevisiae (brewer's yeast)
SequenceString: TSEDGGLTAS DVHPTLGVQL FSAGIAACLA DVITFPLDTA KVRLQVQGEC PTSSVIRYKG VLGTITAVVK TEGRMKLYSG LPAGLQRQI SSASLRIGLY DTVQEFLTAG KETAPSLGSK ILAGLTTGGV AVFIGQPTEV VKVRLQAQSH LHGIKPRYTG T YNAYRIIA ...String:
TSEDGGLTAS DVHPTLGVQL FSAGIAACLA DVITFPLDTA KVRLQVQGEC PTSSVIRYKG VLGTITAVVK TEGRMKLYSG LPAGLQRQI SSASLRIGLY DTVQEFLTAG KETAPSLGSK ILAGLTTGGV AVFIGQPTEV VKVRLQAQSH LHGIKPRYTG T YNAYRIIA TTEGLTGLWK GTTPNLMRSV IINCTELVTY DLMKEAFVKN NILADDVPCH LVSALIAGFC ATAMSSPVDV VK TRFINSP PGQYKSVPNC AMKVFTNEGP TAFFKGLVPS FLRLGSWNVI MFVCFEQLKR ELSKSRQTMD CAT

UniProtKB: Mitochondrial brown fat uncoupling protein 1

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Macromolecule #2: CA9871

MacromoleculeName: CA9871 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Lama glama (llama)
Molecular weightTheoretical: 13.423773 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
QVQLVESGGG LVQAGDSLRL SCAASGLTLK NYAMGWFRQA PGKEHEFVAV ISWSGSGTSY ADSVEGRFTI SRDNAKNTAF LQMSSLKPE DTAVYYCAAR DGGYGSRWPD EYTYWGQGTQ VTVPP

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Macromolecule #3: CA9865

MacromoleculeName: CA9865 / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Lama glama (llama)
Molecular weightTheoretical: 14.02268 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
QVQLVESGGG LVQAGGSLRL SCAPSGRTSS TYTMGWFRQA PGKEREFVAA ISWTGTPYYA DSVKGRFTIS RDNAKNTVYL QMNSLKPED TAVYYCAAAR PGLFIFVSDY ARTAKYDYWG QGTQVTVPP

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Macromolecule #4: URIDINE 5'-TRIPHOSPHATE

MacromoleculeName: URIDINE 5'-TRIPHOSPHATE / type: ligand / ID: 4 / Number of copies: 1 / Formula: UTP
Molecular weightTheoretical: 484.141 Da
Chemical component information

ChemComp-UTP:
URIDINE 5'-TRIPHOSPHATE / UTP*YM

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Macromolecule #5: CARDIOLIPIN

MacromoleculeName: CARDIOLIPIN / type: ligand / ID: 5 / Number of copies: 3 / Formula: CDL
Molecular weightTheoretical: 1.464043 KDa
Chemical component information

ChemComp-CDL:
CARDIOLIPIN / 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

Concentration3 mg/mL
BufferpH: 6
Component:
ConcentrationName
20.0 mMMES
150.0 mMNaCl
0.02 %Lauryl maltose neopentyl glycol
0.02 mg/mLTetraoleoyl cardiolipin
1.0 mMTCEP
2.0 mMMaltose
2.0 mMUTP
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300
VitrificationCryogen name: ETHANE / Chamber humidity: 95 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN 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: 70.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 1.8 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: PDB ENTRY
PDB model - PDB ID:

8g8w

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.03 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 705820
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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