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- EMDB-27434: Leptin-bound leptin receptor complex- focused interaction -

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Basic information

Entry
Database: EMDB / ID: EMD-27434
TitleLeptin-bound leptin receptor complex- focused interaction
Map dataLeptin-bound leptin receptor complex- focused interaction
Sample
  • Complex: Leptin Receptor Complex
    • Protein or peptide: Leptin
  • Protein or peptide: Leptin receptor
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
Function / homology
Function and homology information


negative regulation of metabolic process / negative regulation of locomotor rhythm / Synthesis, secretion, and deacylation of Ghrelin / negative regulation of eating behavior / regulation of lipoprotein lipid oxidation / cellular response to L-ascorbic acid / positive regulation of fat cell apoptotic process / negative regulation of glutamine transport / leptin receptor activity / regulation of transport ...negative regulation of metabolic process / negative regulation of locomotor rhythm / Synthesis, secretion, and deacylation of Ghrelin / negative regulation of eating behavior / regulation of lipoprotein lipid oxidation / cellular response to L-ascorbic acid / positive regulation of fat cell apoptotic process / negative regulation of glutamine transport / leptin receptor activity / regulation of transport / negative regulation of appetite by leptin-mediated signaling pathway / negative regulation of glucagon secretion / regulation of endothelial cell proliferation / regulation of natural killer cell proliferation / leptin receptor binding / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / protein-hormone receptor activity / positive regulation of luteinizing hormone secretion / regulation of natural killer cell mediated cytotoxicity / bone growth / regulation of natural killer cell activation / positive regulation of monoatomic ion transport / glycerol biosynthetic process / elastin metabolic process / leptin-mediated signaling pathway / positive regulation of follicle-stimulating hormone secretion / regulation of steroid biosynthetic process / regulation of intestinal cholesterol absorption / regulation of bone remodeling / regulation of brown fat cell differentiation / positive regulation of peroxisome proliferator activated receptor signaling pathway / adult feeding behavior / positive regulation of hepatic stellate cell activation / response to leptin / regulation of feeding behavior / bone mineralization involved in bone maturation / sexual reproduction / activation of protein kinase C activity / regulation of lipid biosynthetic process / 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 / energy reserve metabolic process / regulation of metabolic process / prostaglandin secretion / bile acid metabolic process / negative regulation of glucose import / tyrosine phosphorylation of STAT protein / cellular response to leptin stimulus / hormone metabolic process / cardiac muscle hypertrophy / regulation of protein localization to nucleus / insulin secretion / cytokine receptor activity / intestinal absorption / aorta development / regulation of fat cell differentiation / positive regulation of p38MAPK cascade / peptide hormone receptor binding / negative regulation of vasoconstriction / regulation of nitric-oxide synthase activity / regulation of gluconeogenesis / eating behavior / fatty acid beta-oxidation / glycogen metabolic process / cytokine binding / central nervous system neuron development / regulation of cytokine production involved in inflammatory response / positive regulation of insulin secretion involved in cellular response to glucose stimulus / peptide hormone binding / response to dietary excess / regulation of insulin secretion / negative regulation of lipid storage / T cell differentiation / positive regulation of TOR signaling / response to vitamin E / glial cell proliferation / adipose tissue development / regulation of angiogenesis / negative regulation of gluconeogenesis / phagocytosis / energy homeostasis / positive regulation of insulin receptor signaling pathway / cellular response to retinoic acid / positive regulation of tyrosine phosphorylation of STAT protein / positive regulation of T cell proliferation / positive regulation of interleukin-12 production / cholesterol metabolic process / negative regulation of autophagy / response to activity / placenta development / female pregnancy / gluconeogenesis / determination of adult lifespan / positive regulation of interleukin-8 production / regulation of protein phosphorylation / positive regulation of receptor signaling pathway via JAK-STAT
Similarity search - Function
Leptin / Leptin / Leptin receptor, immunoglobulin-like domain / Obesity receptor immunoglobulin like domain / Immunoglobulin C2-set-like, ligand-binding / Ig-like C2-type domain / Short hematopoietin receptor, family 1, conserved site / Long hematopoietin receptor, Gp130 family 2, conserved site / Long hematopoietin receptor, gp130 family signature. / Four-helical cytokine-like, core ...Leptin / Leptin / Leptin receptor, immunoglobulin-like domain / Obesity receptor immunoglobulin like domain / Immunoglobulin C2-set-like, ligand-binding / Ig-like C2-type domain / Short hematopoietin receptor, family 1, conserved site / Long hematopoietin receptor, Gp130 family 2, conserved site / Long hematopoietin receptor, gp130 family signature. / Four-helical cytokine-like, core / Fibronectin type 3 domain / Fibronectin type-III domain profile. / Fibronectin type III / Fibronectin type III superfamily / Ig-like domain profile. / Immunoglobulin-like domain / Immunoglobulin-like fold
Similarity search - Domain/homology
Leptin / Leptin receptor
Similarity search - Component
Biological speciesMus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.8 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-
UpdateApr 19, 2023-
Current statusApr 19, 2023Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_27434.png

Downloads & links

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Map

FileDownload / File: emd_27434.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationLeptin-bound leptin receptor complex- focused interaction
Voxel sizeX=Y=Z: 1.19294 Å
Density
Contour LevelBy AUTHOR: 0.2
Minimum - Maximum-1.3756517 - 1.7643884
Average (Standard dev.)0.0004436446 (±0.014056075)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 381.74078 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_27434_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Leptin-bound leptin receptor complex- focused interaction

Fileemd_27434_half_map_1.map
AnnotationLeptin-bound leptin receptor complex- focused interaction
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Leptin-bound leptin receptor complex- focused interaction

Fileemd_27434_half_map_2.map
AnnotationLeptin-bound leptin receptor complex- focused interaction
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

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
  • Protein or peptide: Leptin receptor
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: Leptin Receptor Complex

SupramoleculeName: Leptin Receptor Complex / type: complex / ID: 1 / Chimera: Yes / Parent: 0 / Macromolecule list: #2
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: 63.445523 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: DVVYFPPKIL TSVGSNASFH CIYKNENQII SSKQIVWWRN LAEKIPEIQY SIVSDRVSKV TFSNLKATRP RGKFTYDAVY CCNEQACHH RYAELYVIDV NINISCETDG YLTKMTCRWS PSTIQSLVGS TVQLRYHRRS LYCPDSPSIH PTSEPKNCVL Q RDGFYECV ...String:
DVVYFPPKIL TSVGSNASFH CIYKNENQII SSKQIVWWRN LAEKIPEIQY SIVSDRVSKV TFSNLKATRP RGKFTYDAVY CCNEQACHH RYAELYVIDV NINISCETDG YLTKMTCRWS PSTIQSLVGS TVQLRYHRRS LYCPDSPSIH PTSEPKNCVL Q RDGFYECV FQPIFLLSGY TMWIRINHSL GSLDSPPTCV LPDSVVKPLP PSNVKAEITV NTGLLKVSWE KPVFPENNLQ FQ IRYGLSG KEIQWKTHEV FDAKSKSASL LVSDLCAVYV VQVRCRRLDG LGYWSNWSSP AYTLVMDVKV PMRGPEFWRK MDG DVTKKE RNVTLLWKPL TKNDSLCSVR RYVVKHRTAH NGTWSEDVGN RTNLTFLWTE PAHTVTVLAV NSLGASLVNF NLTF SWPMS KVSAVESLSA YPLSSSCVIL SWTLSPDDYS LLYLVIEWKI LNEDDGMKWL RIPSNVKKFY IHDNFIPIEK YQFSL YPVF MEGVGKPKII NGFTKDAIDK QQNDAGGSGG MKQLEDKVEE LLSKNYHLEN EVARLKKLVG ERSGGHHHHH H

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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: 16.018284 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
VPIQKVQDDT KTLIKTIVTR INDISHTQSV SAKQRVTGLD FIPGLHPILS LSKMDQTLAV YQQVLTSLPS QNVLQIANDL ENLRDLLHL LAFSKSCSLP QTSGLQKPES LDGVLEASLY STEVVALSRL QGSLQDILQQ LDVSPEC

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Macromolecule #3: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 3 / Number of copies: 2 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

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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
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
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
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 53.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Initial angle assignmentType: OTHER
Final angle assignmentType: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.8 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 460818
FSC plot (resolution estimation)

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