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- PDB-9fzq: Proton conductance by human uncoupling protein 1 is inhibited by ... -

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Basic information

Entry
Database: PDB / ID: 9fzq
TitleProton conductance by human uncoupling protein 1 is inhibited by both purine and pyrimidine nucleotides
Components
  • CA9865
  • CA9871
  • Mitochondrial brown fat uncoupling protein 1
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
CARDIOLIPIN / URIDINE 5'-TRIPHOSPHATE / Mitochondrial brown fat uncoupling protein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Lama glama (llama)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.03 Å
AuthorsJones, S.A. / Sowton, A.P. / Lacabanne, D. / King, M.S. / Palmer, S.M. / Zogg, T. / Pardon, E. / Steyaert, J. / Ruprecht, J.J. / Kunji, E.R.S.
Funding support United Kingdom, European Union, Belgium, 3items
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, 2024Deposition site: PDBE / Processing site: PDBE
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: FSC / Data content type: FSC / 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: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Mar 12, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
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Revision 1.1Mar 12, 2025Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Database references / Experimental summary / Data content type: EM metadata / EM metadata / EM metadata / 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
A: Mitochondrial brown fat uncoupling protein 1
B: CA9871
C: CA9865
hetero molecules


Theoretical massNumber of molelcules
Total (without water)65,6627
Polymers60,7863
Non-polymers4,8764
Water00
1


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

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Components

#1: Protein Mitochondrial brown fat uncoupling protein 1 / UCP 1 / Solute carrier family 25 member 7 / Thermogenin


Mass: 33339.629 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: UCP1, SLC25A7, UCP / Production host: Saccharomyces cerevisiae (brewer's yeast) / References: UniProt: P25874
#2: Antibody CA9871


Mass: 13423.773 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Lama glama (llama) / Production host: Escherichia coli (E. coli)
#3: Antibody CA9865


Mass: 14022.680 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Lama glama (llama) / Production host: Escherichia coli (E. coli)
#4: Chemical ChemComp-UTP / URIDINE 5'-TRIPHOSPHATE


Mass: 484.141 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C9H15N2O15P3 / Feature type: SUBJECT OF INVESTIGATION / Comment: UTP*YM
#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.: 3 / Source method: obtained synthetically / Formula: C81H156O17P2 / Comment: phospholipid*YM
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: UCP1 bound to UTP and in complex with two Pro-macrobodies
Type: COMPLEX / Entity ID: #1-#3 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Saccharomyces cerevisiae (brewer's yeast)
Buffer solutionpH: 6
Buffer component
IDConc.NameBuffer-ID
120 mMMES1
2150 mMNaCl1
30.02 %Lauryl maltose neopentyl glycol1
40.02 mg/mLTetraoleoyl cardiolipin1
51 mMTCEP1
62 mMMaltose1
72 mMUTP1
SpecimenConc.: 3 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 95 % / Chamber temperature: 277 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1800 nm / Nominal defocus min: 800 nm / Cs: 2.7 mm / C2 aperture diameter: 70 µm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.03 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 705820 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0074178
ELECTRON MICROSCOPYf_angle_d0.7935692
ELECTRON MICROSCOPYf_dihedral_angle_d14.2931491
ELECTRON MICROSCOPYf_chiral_restr0.052640
ELECTRON MICROSCOPYf_plane_restr0.014717

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