+Open data
-Basic information
Entry | Database: PDB / ID: 8dh8 | ||||||
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Title | Leptin-bound leptin receptor complex-full ECD | ||||||
Components |
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Keywords | HORMONE / Ob / receptor / cytokine / 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 | ||||||
Biological species | Mus musculus (house mouse) | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 5.9 Å | ||||||
Authors | Saxton, R.A. / Caveney, N.A. / Garcia, K.C. | ||||||
Funding support | United States, 1items
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Citation | Journal: 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 |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 8dh8.cif.gz | 235.3 KB | Display | PDBx/mmCIF format |
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PDB format | pdb8dh8.ent.gz | 156.1 KB | Display | PDB format |
PDBx/mmJSON format | 8dh8.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 8dh8_validation.pdf.gz | 1.3 MB | Display | wwPDB validaton report |
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Full document | 8dh8_full_validation.pdf.gz | 1.3 MB | Display | |
Data in XML | 8dh8_validation.xml.gz | 49.5 KB | Display | |
Data in CIF | 8dh8_validation.cif.gz | 76.5 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/dh/8dh8 ftp://data.pdbj.org/pub/pdb/validation_reports/dh/8dh8 | HTTPS FTP |
-Related structure data
Related structure data | 27432MC 8dh9C 8dhaC M: map data used to model this data C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
#1: Protein | Mass: 97375.273 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 | | Mass: 15502.702 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 |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
Component | Name: Leptin Receptor Complex / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT |
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Molecular weight | Experimental value: NO |
Source (natural) | Organism: Mus musculus (house mouse) |
Source (recombinant) | Organism: Homo sapiens (human) |
Buffer solution | pH: 7.2 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Specimen support | Grid material: GOLD / Grid mesh size: 200 divisions/in. / Grid type: Quantifoil R1.2/1.3 |
Vitrification | Cryogen name: ETHANE |
-Electron microscopy imaging
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: TFS KRIOS |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: OTHER |
Electron lens | Mode: OTHER / Nominal defocus max: 2000 nm / Nominal defocus min: 800 nm |
Image recording | Electron dose: 53 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) |
-Processing
Software | Name: PHENIX / Version: 1.20_4459: / Classification: refinement |
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION |
3D reconstruction | Resolution: 5.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 270721 / Symmetry type: POINT |
Refinement | Highest resolution: 5.9 Å |