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- PDB-8dha: Leptin-bound leptin receptor complex- focused interaction -

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Basic information

Entry
Database: PDB / ID: 8dha
TitleLeptin-bound leptin receptor complex- focused interaction
Components
  • Leptin
  • Leptin receptor
KeywordsHORMONE / leptin / receptor / complex
Function / homology
Function and homology information


Synthesis, secretion, and deacylation of Ghrelin / leptin receptor activity / regulation of transport / 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 / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / negative regulation of glucagon secretion ...Synthesis, secretion, and deacylation of Ghrelin / leptin receptor activity / regulation of transport / 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 / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / negative regulation of glucagon secretion / regulation of endothelial cell proliferation / regulation of natural killer cell proliferation / regulation of natural killer cell mediated cytotoxicity / leptin receptor binding / regulation of bone remodeling / positive regulation of luteinizing hormone secretion / bone growth / regulation of natural killer cell activation / glycerol biosynthetic process / regulation of steroid biosynthetic process / elastin metabolic process / leptin-mediated signaling pathway / positive regulation of follicle-stimulating hormone secretion / positive regulation of monoatomic ion transport / regulation of intestinal cholesterol absorption / positive regulation of hepatic stellate cell activation / regulation of feeding behavior / regulation of brown fat cell differentiation / positive regulation of peroxisome proliferator activated receptor signaling pathway / regulation of nitric-oxide synthase activity / adult feeding behavior / activation of protein kinase C activity / bone mineralization involved in bone maturation / regulation of lipid biosynthetic process / sexual reproduction / response to leptin / negative regulation of cartilage development / ovulation from ovarian follicle / negative regulation of D-glucose import / negative regulation of appetite / positive regulation of developmental growth / energy reserve metabolic process / leukocyte tethering or rolling / bile acid metabolic process / cellular response to leptin stimulus / prostaglandin secretion / cardiac muscle hypertrophy / positive regulation of p38MAPK cascade / hormone metabolic process / regulation of protein localization to nucleus / cell surface receptor signaling pathway via STAT / regulation of fat cell differentiation / intestinal absorption / eating behavior / insulin secretion / regulation of metabolic process / aorta development / regulation of gluconeogenesis / negative regulation of vasoconstriction / response to vitamin E / glycogen metabolic process / peptide hormone receptor binding / fatty acid beta-oxidation / regulation of cytokine production involved in inflammatory response / central nervous system neuron development / response to dietary excess / peptide hormone binding / T cell differentiation / negative regulation of lipid storage / positive regulation of TOR signaling / regulation of angiogenesis / cell surface receptor signaling pathway via JAK-STAT / negative regulation of gluconeogenesis / positive regulation of insulin receptor signaling pathway / adipose tissue development / phagocytosis / glial cell proliferation / cholesterol metabolic process / energy homeostasis / cellular response to retinoic acid / positive regulation of T cell proliferation / positive regulation of interleukin-12 production / regulation of insulin secretion / negative regulation of autophagy / placenta development / response to activity / gluconeogenesis / determination of adult lifespan / positive regulation of interleukin-8 production / positive regulation of receptor signaling pathway via JAK-STAT / female pregnancy / response to insulin / circadian rhythm / hormone activity / positive regulation of interleukin-6 production / positive regulation of protein import into nucleus / lipid metabolic process / regulation of blood pressure / glucose metabolic process / cellular response to insulin stimulus
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. / Growth Hormone; Chain: A; - #10 ...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. / Growth Hormone; Chain: A; - #10 / Four-helical cytokine-like, core / Growth Hormone; Chain: A; / 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 / Immunoglobulins / Up-down Bundle / Immunoglobulin-like / Sandwich / Mainly Beta / Mainly Alpha
Similarity search - Domain/homology
Leptin / Leptin receptor
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.8 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: FSC / Data content type: FSC / 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
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Revision 1.0Apr 19, 2023Data content type: FSC / Data content type: FSC / 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 9, 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 / _pdbx_entry_details.has_protein_modification
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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)143,3525
Polymers142,9093
Non-polymers4422
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: 63445.523 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: 16018.284 Da / Num. of mol.: 1
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
#3: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0
Has ligand of interestN
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: #2 / 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

Software
NameVersionClassification
phenix.real_space_refine1.17.1_3660refinement
PHENIX1.17.1_3660refinement
EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 460818 / Symmetry type: POINT
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 204.4 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00373588
ELECTRON MICROSCOPYf_angle_d0.7894884
ELECTRON MICROSCOPYf_chiral_restr0.0449572
ELECTRON MICROSCOPYf_plane_restr0.0053614
ELECTRON MICROSCOPYf_dihedral_angle_d17.20591328

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