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- EMDB-27432: Leptin-bound leptin receptor complex-full ECD -

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Basic information

Entry
Database: EMDB / ID: EMD-27432
TitleLeptin-bound leptin receptor complex-full ECD
Map dataLeptin-bound leptin receptor complex-full ECD
Sample
  • Complex: Leptin Receptor Complex
    • Protein or peptide: Leptin receptor
    • Protein or peptide: Leptin
KeywordsOb / receptor / cytokine / hormone / signaling protein
Function / homology
Function and homology information


negative regulation of metabolic process / regulation of lipoprotein lipid oxidation / cellular response to L-ascorbic acid / positive regulation of fat cell apoptotic process / negative regulation of glutamine transport / negative regulation of appetite by leptin-mediated signaling pathway / negative regulation of glucagon secretion / regulation of endothelial cell proliferation / Synthesis, secretion, and deacylation of Ghrelin / regulation of natural killer cell proliferation ...negative regulation of metabolic process / regulation of lipoprotein lipid oxidation / cellular response to L-ascorbic acid / positive regulation of fat cell apoptotic process / negative regulation of glutamine transport / negative regulation of appetite by leptin-mediated signaling pathway / negative regulation of glucagon secretion / regulation of endothelial cell proliferation / Synthesis, secretion, and deacylation of Ghrelin / regulation of natural killer cell proliferation / leptin receptor binding / positive regulation of luteinizing hormone secretion / regulation of natural killer cell mediated cytotoxicity / regulation of natural killer cell activation / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / glycerol biosynthetic process / positive regulation of monoatomic ion transport / elastin metabolic process / regulation of steroid biosynthetic process / bone growth / positive regulation of follicle-stimulating hormone secretion / regulation of intestinal cholesterol absorption / leptin-mediated signaling pathway / regulation of brown fat cell differentiation / positive regulation of peroxisome proliferator activated receptor signaling pathway / positive regulation of hepatic stellate cell activation / regulation of bone remodeling / adult feeding behavior / regulation of nitric-oxide synthase activity / bone mineralization involved in bone maturation / activation of protein kinase C activity / regulation of lipid biosynthetic process / sexual reproduction / negative regulation of cartilage development / fatty acid catabolic process / ovulation from ovarian follicle / negative regulation of appetite / positive regulation of developmental growth / leukocyte tethering or rolling / cellular response to leptin stimulus / prostaglandin secretion / bile acid metabolic process / negative regulation of D-glucose import / energy reserve metabolic process / tyrosine phosphorylation of STAT protein / hormone metabolic process / cardiac muscle hypertrophy / regulation of protein localization to nucleus / regulation of metabolic process / aorta development / intestinal absorption / insulin secretion / regulation of fat cell differentiation / positive regulation of p38MAPK cascade / negative regulation of vasoconstriction / eating behavior / peptide hormone receptor binding / regulation of gluconeogenesis / fatty acid beta-oxidation / regulation of cytokine production involved in inflammatory response / central nervous system neuron development / regulation of insulin secretion / response to dietary excess / negative regulation of lipid storage / T cell differentiation / positive regulation of TOR signaling / response to vitamin E / regulation of angiogenesis / adipose tissue development / cellular response to retinoic acid / phagocytosis / positive regulation of tyrosine phosphorylation of STAT protein / positive regulation of insulin receptor signaling pathway / positive regulation of T cell proliferation / energy homeostasis / positive regulation of interleukin-12 production / cholesterol metabolic process / negative regulation of autophagy / determination of adult lifespan / response to activity / positive regulation of interleukin-8 production / female pregnancy / positive regulation of receptor signaling pathway via JAK-STAT / regulation of protein phosphorylation / response to insulin / placenta development / lipid metabolic process / hormone activity / regulation of blood pressure / cellular response to insulin stimulus / positive regulation of interleukin-6 production / positive regulation of protein import into nucleus / circadian rhythm / glucose metabolic process / positive regulation of tumor necrosis factor production / positive regulation of reactive oxygen species metabolic process / positive regulation of cold-induced thermogenesis / response to estradiol / glucose homeostasis / angiogenesis
Similarity search - Function
Leptin / Leptin / Four-helical cytokine-like, core
Similarity search - Domain/homology
Biological speciesMus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 5.9 Å
AuthorsSaxton RA / Caveney NA / Garcia KC
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID) United States
CitationJournal: Nat Commun / Year: 2023
Title: Structural insights into the mechanism of leptin receptor activation.
Authors: Robert A Saxton / Nathanael A Caveney / Maria Dolores Moya-Garzon / Karsten D Householder / Grayson E Rodriguez / Kylie A Burdsall / Jonathan Z Long / K Christopher Garcia /
Abstract: Leptin is an adipocyte-derived protein hormone that promotes satiety and energy homeostasis by activating the leptin receptor (LepR)-STAT3 signaling axis in a subset of hypothalamic neurons. Leptin ...Leptin is an adipocyte-derived protein hormone that promotes satiety and energy homeostasis by activating the leptin receptor (LepR)-STAT3 signaling axis in a subset of hypothalamic neurons. Leptin signaling is dysregulated in obesity, however, where appetite remains elevated despite high levels of circulating leptin. To gain insight into the mechanism of leptin receptor activation, here we determine the structure of a stabilized leptin-bound LepR signaling complex using single particle cryo-EM. The structure reveals an asymmetric architecture in which a single leptin induces LepR dimerization via two distinct receptor-binding sites. Analysis of the leptin-LepR binding interfaces reveals the molecular basis for human obesity-associated mutations. Structure-based design of leptin variants that destabilize the asymmetric LepR dimer yield both partial and biased agonists that partially suppress STAT3 activation in the presence of wild-type leptin and decouple activation of STAT3 from LepR negative regulators. Together, these results reveal the structural basis for LepR activation and provide insights into the differential plasticity of signaling pathways downstream of LepR.
History
DepositionJun 25, 2022-
Header (metadata) releaseApr 19, 2023-
Map releaseApr 19, 2023-
UpdateJun 12, 2024-
Current statusJun 12, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_27432.png

Downloads & links

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Map

FileDownload / File: emd_27432.map.gz / Format: CCP4 / Size: 512 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationLeptin-bound leptin receptor complex-full ECD
Projections & slices

Image control

Size
Brightness
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Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.65 Å/pix.
x 512 pix.
= 334.336 Å		0.65 Å/pix.
x 512 pix.
= 334.336 Å		0.65 Å/pix.
x 512 pix.
= 334.336 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.653 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.005
Minimum - Maximum-0.06957991 - 0.07576591
Average (Standard dev.)0.000059688406 (±0.0013827623)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions512512512
Spacing512512512
CellA=B=C: 334.336 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_27432_msk_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
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Histogram

Histogram (log scale)

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Half map: Leptin-bound leptin receptor complex-full ECD

Fileemd_27432_half_map_1.map
AnnotationLeptin-bound leptin receptor complex-full ECD
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Leptin-bound leptin receptor complex-full ECD

Fileemd_27432_half_map_2.map
AnnotationLeptin-bound leptin receptor complex-full ECD
Projections & Slices
AxesZYX

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Slices (1/2)
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Histogram

Histogram (log scale)

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Sample components

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Entire : Leptin Receptor Complex

EntireName: Leptin Receptor Complex
Components
  • Complex: Leptin Receptor Complex
    • Protein or peptide: Leptin receptor
    • Protein or peptide: Leptin

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Supramolecule #1: Leptin Receptor Complex

SupramoleculeName: Leptin Receptor Complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Mus musculus (house mouse)

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Macromolecule #1: Leptin receptor

MacromoleculeName: Leptin receptor / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 97.375273 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: LNLAYPISPW KFKLFCGPPN TTDDSFLSPA GAPNNASALK GASEAIVEAK FNSSGIYVPE LSKTVFHCCF GNEQGQNCSA LTDNTEGKT LASVVKASVF RQLGVNWDIE CWMKGDLTLF ICHMEPLPKN PFKNYDSKVH LLYDLPEVID DSPLPPLKDS F QTVQCNCS ...String:
LNLAYPISPW KFKLFCGPPN TTDDSFLSPA GAPNNASALK GASEAIVEAK FNSSGIYVPE LSKTVFHCCF GNEQGQNCSA LTDNTEGKT LASVVKASVF RQLGVNWDIE CWMKGDLTLF ICHMEPLPKN PFKNYDSKVH LLYDLPEVID DSPLPPLKDS F QTVQCNCS LRGCECHVPV PRAKLNYALL MYLEITSAGV SFQSPLMSLQ PMLVVKPDPP LGLHMEVTDD GNLKISWDSQ TM APFPLQY QVKYLENSTI VREAAEIVSA TSLLVDSVLP GSSYEVQVRS KRLDGSGVWS DWSSPQVFTT QDVVYFPPKI LTS VGSNAS FHCIYKNENQ IISSKQIVWW RNLAEKIPEI QYSIVSDRVS KVTFSNLKAT RPRGKFTYDA VYCCNEQACH HRYA ELYVI DVNINISCET DGYLTKMTCR WSPSTIQSLV GSTVQLRYHR RSLYCPDSPS IHPTSEPKNC VLQRDGFYEC VFQPI FLLS GYTMWIRINH SLGSLDSPPT CVLPDSVVKP LPPSNVKAEI TVNTGLLKVS WEKPVFPENN LQFQIRYGLS GKEIQW KTH EVFDAKSKSA SLLVSDLCAV YVVQVRCRRL DGLGYWSNWS SPAYTLVMDV KVPMRGPEFW RKMDGDVTKK ERNVTLL WK PLTKNDSLCS VRRYVVKHRT AHNGTWSEDV GNRTNLTFLW TEPAHTVTVL AVNSLGASLV NFNLTFSWPM SKVSAVES L SAYPLSSSCV ILSWTLSPDD YSLLYLVIEW KILNEDDGMK WLRIPSNVKK FYIHDNFIPI EKYQFSLYPV FMEGVGKPK IINGFTKDAI DKQQNDAGGS GGMKQLEDKV EELLSKNYHL ENEVARLKKL VGERSGGHHH HHH

UniProtKB: UNIPROTKB: P48356

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Macromolecule #2: Leptin

MacromoleculeName: Leptin / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 15.502702 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
VPIQKVQDDT KTLIKTIVTR INDISHTQSV SAKQRVTGLD FIPGLHPILS LSKMDQTLAV YQQVLTSLPS QNVLQIANDL ENLRDLLHL LAFSKSCSLP QTSGLQKPES LDGVLEASLY STEVVALSRL QGSLQDILQQ LD

UniProtKB: Leptin

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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: 7.2
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 200 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 45 sec.
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 53.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: OTHER / Nominal defocus max: 2.0 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: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 5.9 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 270721
Initial angle assignmentType: OTHER
Final angle assignmentType: OTHER
FSC plot (resolution estimation)

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