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- PDB-8dh9: Leptin-bound leptin receptor complex-D3-D7 -

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Basic information

Entry
Database: PDB / ID: 8dh9
TitleLeptin-bound leptin receptor complex-D3-D7
Components
  • Leptin
  • Leptin receptor
KeywordsHORMONE / leptin / receptor / complex
Function / homology
Function and homology information


negative regulation of metabolic process / negative regulation of locomotor rhythm / Synthesis, secretion, and deacylation of Ghrelin / leptin receptor activity / regulation of lipoprotein lipid oxidation / cellular response to L-ascorbic acid / positive regulation of fat cell apoptotic process / negative regulation of glutamine transport / activation of protein kinase C activity / negative regulation of appetite by leptin-mediated signaling pathway ...negative regulation of metabolic process / negative regulation of locomotor rhythm / Synthesis, secretion, and deacylation of Ghrelin / leptin receptor activity / regulation of lipoprotein lipid oxidation / cellular response to L-ascorbic acid / positive regulation of fat cell apoptotic process / negative regulation of glutamine transport / activation of protein kinase C activity / negative regulation of appetite by leptin-mediated signaling pathway / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / negative regulation of glucagon secretion / regulation of endothelial cell proliferation / leptin receptor binding / regulation of natural killer cell mediated cytotoxicity / regulation of bone remodeling / regulation of natural killer cell proliferation / positive regulation of luteinizing hormone secretion / sexual reproduction / regulation of natural killer cell activation / glycerol biosynthetic process / regulation of steroid biosynthetic process / negative regulation of eating behavior / elastin metabolic process / regulation of transport / leptin-mediated signaling pathway / positive regulation of follicle-stimulating hormone secretion / positive regulation of monoatomic ion transport / bone growth / protein-hormone receptor activity / regulation of intestinal cholesterol absorption / regulation of brown fat cell differentiation / positive regulation of hepatic stellate cell activation / positive regulation of peroxisome proliferator activated receptor signaling pathway / regulation of nitric-oxide synthase activity / regulation of feeding behavior / adult feeding behavior / bone mineralization involved in bone maturation / response to leptin / regulation of lipid biosynthetic process / fatty acid catabolic process / negative regulation of cartilage development / negative regulation of D-glucose import across plasma membrane / negative regulation of appetite / ovulation from ovarian follicle / positive regulation of developmental growth / energy reserve metabolic process / leukocyte tethering or rolling / prostaglandin secretion / cellular response to leptin stimulus / cardiac muscle hypertrophy / bile acid metabolic process / hormone metabolic process / positive regulation of p38MAPK cascade / cell surface receptor signaling pathway via STAT / regulation of protein localization to nucleus / cytokine receptor activity / regulation of fat cell differentiation / intestinal absorption / insulin secretion / regulation of gluconeogenesis / aorta development / negative regulation of vasoconstriction / eating behavior / response to vitamin E / glycogen metabolic process / peptide hormone receptor binding / fatty acid beta-oxidation / regulation of cytokine production involved in inflammatory response / response to dietary excess / cytokine binding / central nervous system neuron development / regulation of insulin secretion / peptide hormone binding / T cell differentiation / negative regulation of lipid storage / positive regulation of TOR signaling / regulation of angiogenesis / negative regulation of gluconeogenesis / adipose tissue development / positive regulation of insulin receptor signaling pathway / phagocytosis / cell surface receptor signaling pathway via JAK-STAT / glial cell proliferation / cholesterol metabolic process / cellular response to retinoic acid / energy homeostasis / positive regulation of interleukin-12 production / positive regulation of T cell proliferation / placenta development / positive regulation of insulin secretion involved in cellular response to glucose stimulus / response to activity / negative regulation of autophagy / determination of adult lifespan / positive regulation of interleukin-8 production / positive regulation of receptor signaling pathway via JAK-STAT / lipid metabolic process / female pregnancy / circadian rhythm / hormone activity
Similarity search - Function
Leptin / Leptin receptor, immunoglobulin-like domain / Leptin / Obesity receptor immunoglobulin like domain / Short hematopoietin receptor, family 1, conserved site / Immunoglobulin C2-set-like, ligand-binding / Ig-like C2-type domain / Long hematopoietin receptor, Gp130 family 2, conserved site / Long hematopoietin receptor, gp130 family signature. / Four-helical cytokine-like, core ...Leptin / Leptin receptor, immunoglobulin-like domain / Leptin / Obesity receptor immunoglobulin like domain / Short hematopoietin receptor, family 1, conserved site / Immunoglobulin C2-set-like, ligand-binding / Ig-like C2-type domain / Long hematopoietin receptor, Gp130 family 2, conserved site / Long hematopoietin receptor, gp130 family signature. / Four-helical cytokine-like, core / Fibronectin type III domain / 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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4.5 Å
AuthorsSaxton, R.A. / Caveney, N.A. / Garcia, K.C.
Funding support United States, 1items
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, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 19, 2023Provider: repository / Type: Initial release
Revision 1.0Apr 19, 2023Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Apr 19, 2023Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
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Revision 1.0Apr 19, 2023Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Apr 19, 2023Data content type: Mask / Data content type: Mask / Provider: repository / Type: Initial release
Revision 1.0Apr 19, 2023Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.0Apr 19, 2023Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Apr 19, 2023Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Apr 19, 2023Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Apr 19, 2023Data content type: Mask / Data content type: Mask / Provider: repository / Type: Initial release
Revision 1.0Apr 19, 2023Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Oct 23, 2024Group: Data collection / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update
Revision 1.2May 21, 2025Group: Data collection / Category: em_admin / em_software / Item: _em_admin.last_update / _em_software.name
Revision 1.1May 21, 2025Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Data processing / Experimental summary / Data content type: EM metadata / EM metadata / Category: em_admin / em_software / Data content type: EM metadata / EM metadata / Item: _em_admin.last_update / _em_software.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Leptin receptor
B: Leptin receptor
C: Leptin
D: Leptin


Theoretical massNumber of molelcules
Total (without water)164,7994
Polymers164,7994
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Leptin receptor / LEP-R / B219 / OB receptor / OB-R


Mass: 63674.754 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Lepr, Db, Obr / Production host: Homo sapiens (human) / References: UniProt: P48356
#2: Protein Leptin / Obesity factor


Mass: 18724.555 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Lep, Ob / Production host: Homo sapiens (human) / References: UniProt: P41160
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: Leptin Receptor Complex / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Mus musculus (house mouse)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.2
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: OTHER
Electron lensMode: OTHER / Nominal defocus max: 2000 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 53 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.20_4459: / Classification: refinement
EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 4.5 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 137338 / Symmetry type: POINT

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