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- EMDB-29857: Molecular mechanism of nucleotide inhibition of human uncoupling ... -

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Basic information

Entry
Database: EMDB / ID: EMD-29857
TitleMolecular mechanism of nucleotide inhibition of human uncoupling protein 1
Map data
Sample
  • Complex: Complex of human uncoupling protein 1 with two promacrobodies
    • Protein or peptide: Mitochondrial brown fat uncoupling protein 1
    • Protein or peptide: Pro-macrobody 71, Maltose/maltodextrin-binding periplasmic protein chimera
    • Protein or peptide: Pro-Macrobody 65, Maltose/maltodextrin-binding periplasmic protein chimera
  • Ligand: GUANOSINE-5'-TRIPHOSPHATE
  • Ligand: CARDIOLIPIN
KeywordsSLC25 / mitochondrial carrier / uncoupling / MEMBRANE 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 cold ...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 cold / cellular response to fatty acid / response to temperature stimulus / long-chain fatty acid binding / detection of maltose stimulus / maltose transport complex / diet induced thermogenesis / maltose binding / carbohydrate transport / maltose transport / maltodextrin transmembrane transport / proton transmembrane transporter activity / transmembrane transporter activity / carbohydrate transmembrane transporter activity / ATP-binding cassette (ABC) transporter complex, substrate-binding subunit-containing / brown fat cell differentiation / Transcriptional regulation of brown and beige adipocyte differentiation by EBF2 / cellular response to hormone stimulus / response to cold / ATP-binding cassette (ABC) transporter complex / proton transmembrane transport / response to nutrient levels / cell chemotaxis / cellular response to reactive oxygen species / GDP binding / positive regulation of cold-induced thermogenesis / outer membrane-bounded periplasmic space / periplasmic space / mitochondrial inner membrane / DNA damage response / regulation of transcription by RNA polymerase II / GTP binding / mitochondrion / membrane
Similarity search - Function
: / Mitochondrial carrier protein / Mitochondrial substrate/solute carrier / Mitochondrial carrier domain superfamily / Mitochondrial carrier protein / Solute carrier (Solcar) repeat profile. / Maltose/Cyclodextrin ABC transporter, substrate-binding protein / Solute-binding family 1, conserved site / Bacterial extracellular solute-binding proteins, family 1 signature. / Bacterial extracellular solute-binding protein / Bacterial extracellular solute-binding protein
Similarity search - Domain/homology
Maltose/maltodextrin-binding periplasmic protein / Mitochondrial brown fat uncoupling protein 1
Similarity search - Component
Biological speciesHomo sapiens (human) / Escherichia coli (strain K12) (bacteria)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.8 Å
AuthorsGogoi P / Jones SA / Ruprecht JJ / King MS / Lee Y / Zogg T / Pardon E / Chand D / Steimle S / Copeman D ...Gogoi P / Jones SA / Ruprecht JJ / King MS / Lee Y / Zogg T / Pardon E / Chand D / Steimle S / Copeman D / Cotrim CA / Steyaert J / Crichton PG / Moiseenkova-Bell V / Kunji ERS
Funding support United States, United Kingdom, European Union, Belgium, 6 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM144120 United States
Medical Research Council (MRC, United Kingdom)MC_UU_00028/2 United Kingdom
Medical Research Council (MRC, United Kingdom)MC_UU_00015/1 United Kingdom
Biotechnology and Biological Sciences Research Council (BBSRC)BB/S00940X/1 United Kingdom
European Union (EU)Instruct-ERIC/ESFRIEuropean Union
Research Foundation - Flanders (FWO) Belgium
CitationJournal: Sci Adv / Year: 2023
Title: Structural basis of purine nucleotide inhibition of human uncoupling protein 1.
Authors: Scott A Jones / Prerana Gogoi / Jonathan J Ruprecht / Martin S King / Yang Lee / Thomas Zögg / Els Pardon / Deepak Chand / Stefan Steimle / Danielle M Copeman / Camila A Cotrim / Jan ...Authors: Scott A Jones / Prerana Gogoi / Jonathan J Ruprecht / Martin S King / Yang Lee / Thomas Zögg / Els Pardon / Deepak Chand / Stefan Steimle / Danielle M Copeman / Camila A Cotrim / Jan Steyaert / Paul G Crichton / Vera Moiseenkova-Bell / Edmund R S Kunji /
Abstract: Mitochondrial uncoupling protein 1 (UCP1) gives brown adipose tissue of mammals its specialized ability to burn calories as heat for thermoregulation. When activated by fatty acids, UCP1 catalyzes ...Mitochondrial uncoupling protein 1 (UCP1) gives brown adipose tissue of mammals its specialized ability to burn calories as heat for thermoregulation. When activated by fatty acids, UCP1 catalyzes the leak of protons across the mitochondrial inner membrane, short-circuiting the mitochondrion to generate heat, bypassing ATP synthesis. In contrast, purine nucleotides bind and inhibit UCP1, regulating proton leak by a molecular mechanism that is unclear. We present the cryo-electron microscopy structure of the GTP-inhibited state of UCP1, which is consistent with its nonconducting state. The purine nucleotide cross-links the transmembrane helices of UCP1 with an extensive interaction network. Our results provide a structural basis for understanding the specificity and pH dependency of the regulatory mechanism. UCP1 has retained all of the key functional and structural features required for a mitochondrial carrier-like transport mechanism. The analysis shows that inhibitor binding prevents the conformational changes that UCP1 uses to facilitate proton leak.
History
DepositionFeb 20, 2023-
Header (metadata) releaseJun 7, 2023-
Map releaseJun 7, 2023-
UpdateNov 6, 2024-
Current statusNov 6, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_29857.png

Downloads & links

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Map

FileDownload / File: emd_29857.map.gz / Format: CCP4 / Size: 421.9 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.86 Å/pix.
x 480 pix.
= 412.8 Å		0.86 Å/pix.
x 480 pix.
= 412.8 Å		0.86 Å/pix.
x 480 pix.
= 412.8 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.86 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.15
Minimum - Maximum-0.6362561 - 1.2069584
Average (Standard dev.)-0.00006265267 (±0.0116228815)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions480480480
Spacing480480480
CellA=B=C: 412.80002 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_29857_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_29857_half_map_2.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Complex of human uncoupling protein 1 with two promacrobodies

EntireName: Complex of human uncoupling protein 1 with two promacrobodies
Components
  • Complex: Complex of human uncoupling protein 1 with two promacrobodies
    • Protein or peptide: Mitochondrial brown fat uncoupling protein 1
    • Protein or peptide: Pro-macrobody 71, Maltose/maltodextrin-binding periplasmic protein chimera
    • Protein or peptide: Pro-Macrobody 65, Maltose/maltodextrin-binding periplasmic protein chimera
  • Ligand: GUANOSINE-5'-TRIPHOSPHATE
  • Ligand: CARDIOLIPIN

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Supramolecule #1: Complex of human uncoupling protein 1 with two promacrobodies

SupramoleculeName: Complex of human uncoupling protein 1 with two promacrobodies
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: Pro-macrobody 71, Maltose/maltodextrin-binding periplasmic protei...

MacromoleculeName: Pro-macrobody 71, Maltose/maltodextrin-binding periplasmic protein chimera
type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Escherichia coli (strain K12) (bacteria)
Molecular weightTheoretical: 53.45391 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: GPSQVQLVES GGGLVQAGDS LRLSCAASGL TLKNYAMGWF RQAPGKEHEF VAVISWSGSG TSYADSVEGR FTISRDNAKN TAFLQMSSL KPEDTAVYYC AARDGGYGSR WPDEYTYWGQ GTQVTVPPLV IWINGDKGYN GLAEVGKKFE KDTGIKVTVE H PDKLEEKF ...String:
GPSQVQLVES GGGLVQAGDS LRLSCAASGL TLKNYAMGWF RQAPGKEHEF VAVISWSGSG TSYADSVEGR FTISRDNAKN TAFLQMSSL KPEDTAVYYC AARDGGYGSR WPDEYTYWGQ GTQVTVPPLV IWINGDKGYN GLAEVGKKFE KDTGIKVTVE H PDKLEEKF PQVAATGDGP DIIFWAHDRF GGYAQSGLLA EITPDKAFQD KLYPFTWDAV RYNGKLIAYP IAVEALSLIY NK DLLPNPP KTWEEIPALD KELKAKGKSA LMFNLQEPYF TWPLIAADGG YAFKYENGKY DIKDVGVDNA GAKAGLTFLV DLI KNKHMN ADTDYSIAEA AFNKGETAMT INGPWAWSNI DTSKVNYGVT VLPTFKGQPS KPFVGVLSAG INAASPNKEL AKEF LENYL LTDEGLEAVN KDKPLGAVAL KSYEEELAKD PRIAATMENA QKGEIMPNIP QMSAFWYAVR TAVINAASGR QTVDE ALKD AQTPGS

UniProtKB: Maltose/maltodextrin-binding periplasmic protein

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Macromolecule #3: Pro-Macrobody 65, Maltose/maltodextrin-binding periplasmic protei...

MacromoleculeName: Pro-Macrobody 65, Maltose/maltodextrin-binding periplasmic protein chimera
type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Escherichia coli (strain K12) (bacteria)
Molecular weightTheoretical: 54.05282 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: GPSQVQLVES GGGLVQAGGS LRLSCAPSGR TSSTYTMGWF RQAPGKEREF VAAISWTGTP YYADSVKGRF TISRDNAKNT VYLQMNSLK PEDTAVYYCA AARPGLFIFV SDYARTAKYD YWGQGTQVTV PPLVIWINGD KGYNGLAEVG KKFEKDTGIK V TVEHPDKL ...String:
GPSQVQLVES GGGLVQAGGS LRLSCAPSGR TSSTYTMGWF RQAPGKEREF VAAISWTGTP YYADSVKGRF TISRDNAKNT VYLQMNSLK PEDTAVYYCA AARPGLFIFV SDYARTAKYD YWGQGTQVTV PPLVIWINGD KGYNGLAEVG KKFEKDTGIK V TVEHPDKL EEKFPQVAAT GDGPDIIFWA HDRFGGYAQS GLLAEITPDK AFQDKLYPFT WDAVRYNGKL IAYPIAVEAL SL IYNKDLL PNPPKTWEEI PALDKELKAK GKSALMFNLQ EPYFTWPLIA ADGGYAFKYE NGKYDIKDVG VDNAGAKAGL TFL VDLIKN KHMNADTDYS IAEAAFNKGE TAMTINGPWA WSNIDTSKVN YGVTVLPTFK GQPSKPFVGV LSAGINAASP NKEL AKEFL ENYLLTDEGL EAVNKDKPLG AVALKSYEEE LAKDPRIAAT MENAQKGEIM PNIPQMSAFW YAVRTAVINA ASGRQ TVDE ALKDAQTPGS

UniProtKB: Maltose/maltodextrin-binding periplasmic protein

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Macromolecule #5: GUANOSINE-5'-TRIPHOSPHATE

MacromoleculeName: GUANOSINE-5'-TRIPHOSPHATE / type: ligand / ID: 5 / Number of copies: 1 / Formula: GTP
Molecular weightTheoretical: 523.18 Da
Chemical component information

ChemComp-GTP:
GUANOSINE-5'-TRIPHOSPHATE / GTP, energy-carrying molecule*YM

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Macromolecule #6: CARDIOLIPIN

MacromoleculeName: CARDIOLIPIN / type: ligand / ID: 6 / 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:
ConcentrationFormulaName
20.0 mMC6H13NO4SMES
150.0 mMNaClSodium chloride
1.0 mMC9H15O6PTCEP
0.02 %C43H80O22DMNG
0.02 mg/mLC81H150O17P2Tetraoleoyl cardiolipin
2.0 mMC10H16N5O14P3GTP
2.0 mMC12H22O11D-maltose
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277.14 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 72.9 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 0.5 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.8 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 203799
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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