+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-27434 | |||||||||
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Title | Leptin-bound leptin receptor complex- focused interaction | |||||||||
Map data | Leptin-bound leptin receptor complex- focused interaction | |||||||||
Sample |
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Keywords | leptin / receptor / complex / HORMONE | |||||||||
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 | single particle reconstruction / cryo EM / Resolution: 3.8 Å | |||||||||
Authors | Saxton RA / Caveney NA / Garcia KC | |||||||||
Funding support | United States, 1 items
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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
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_27434.map.gz | 11.3 MB | EMDB map data format | |
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Header (meta data) | emd-27434-v30.xml emd-27434.xml | 15.2 KB 15.2 KB | Display Display | EMDB header |
FSC (resolution estimation) | emd_27434_fsc.xml | 10.5 KB | Display | FSC data file |
Images | emd_27434.png | 46.7 KB | ||
Masks | emd_27434_msk_1.map | 125 MB | Mask map | |
Filedesc metadata | emd-27434.cif.gz | 5.7 KB | ||
Others | emd_27434_half_map_1.map.gz emd_27434_half_map_2.map.gz | 115.7 MB 115.7 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-27434 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-27434 | HTTPS FTP |
-Validation report
Summary document | emd_27434_validation.pdf.gz | 811.8 KB | Display | EMDB validaton report |
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Full document | emd_27434_full_validation.pdf.gz | 811.4 KB | Display | |
Data in XML | emd_27434_validation.xml.gz | 18.9 KB | Display | |
Data in CIF | emd_27434_validation.cif.gz | 24.4 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-27434 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-27434 | HTTPS FTP |
-Related structure data
Related structure data | 8dhaMC 8dh8C 8dh9C M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_27434.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||
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Annotation | Leptin-bound leptin receptor complex- focused interaction | ||||||||||||||||||||||||||||||||||||
Projections & slices | Image control
Images are generated by Spider. | ||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 1.19294 Å | ||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Mask #1
File | emd_27434_msk_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: Leptin-bound leptin receptor complex- focused interaction
File | emd_27434_half_map_1.map | ||||||||||||
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Annotation | Leptin-bound leptin receptor complex- focused interaction | ||||||||||||
Projections & Slices |
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Density Histograms |
-Half map: Leptin-bound leptin receptor complex- focused interaction
File | emd_27434_half_map_2.map | ||||||||||||
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Annotation | Leptin-bound leptin receptor complex- focused interaction | ||||||||||||
Projections & Slices |
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Density Histograms |
-Sample components
-Entire : Leptin Receptor Complex
Entire | Name: Leptin Receptor Complex |
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Components |
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-Supramolecule #1: Leptin Receptor Complex
Supramolecule | Name: Leptin Receptor Complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #2 |
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Source (natural) | Organism: Mus musculus (house mouse) |
-Macromolecule #1: Leptin receptor
Macromolecule | Name: Leptin receptor / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO |
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Source (natural) | Organism: Mus musculus (house mouse) |
Molecular weight | Theoretical: 63.445523 KDa |
Recombinant expression | Organism: Homo sapiens (human) |
Sequence | String: 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 UniProtKB: UNIPROTKB: P48356 |
-Macromolecule #2: Leptin
Macromolecule | Name: Leptin / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Mus musculus (house mouse) |
Molecular weight | Theoretical: 16.018284 KDa |
Recombinant expression | Organism: Homo sapiens (human) |
Sequence | String: VPIQKVQDDT KTLIKTIVTR INDISHTQSV SAKQRVTGLD FIPGLHPILS LSKMDQTLAV YQQVLTSLPS QNVLQIANDL ENLRDLLHL LAFSKSCSLP QTSGLQKPES LDGVLEASLY STEVVALSRL QGSLQDILQQ LDVSPEC UniProtKB: Leptin |
-Macromolecule #3: 2-acetamido-2-deoxy-beta-D-glucopyranose
Macromolecule | Name: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 3 / Number of copies: 2 / Formula: NAG |
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Molecular weight | Theoretical: 221.208 Da |
Chemical component information | ChemComp-NAG: |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Buffer | pH: 7.2 |
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Vitrification | Cryogen name: ETHANE |
-Electron microscopy
Microscope | TFS KRIOS |
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Image recording | Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 53.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination 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 |