+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-27433 | |||||||||
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Title | Leptin-bound leptin receptor complex-D3-D7 | |||||||||
Map data | Leptin-bound leptin receptor complex-D3-D7 | |||||||||
Sample |
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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 / 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 / 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 / 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 nitric-oxide synthase activity / bone mineralization involved in bone maturation / sexual reproduction / regulation of feeding behavior / regulation of lipid biosynthetic process / activation of protein kinase C activity / 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 / negative regulation of glucose import / prostaglandin secretion / bile acid metabolic process / tyrosine phosphorylation of STAT protein / cellular response to leptin stimulus / hormone metabolic process / regulation of protein localization to nucleus / cardiac muscle hypertrophy / aorta development / intestinal absorption / insulin secretion / regulation of fat cell differentiation / positive regulation of p38MAPK cascade / peptide hormone receptor binding / cytokine receptor activity / negative regulation of vasoconstriction / eating behavior / regulation of gluconeogenesis / glycogen metabolic process / cytokine binding / fatty acid beta-oxidation / 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 / 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 / glial cell proliferation / regulation of angiogenesis / adipose tissue development / negative regulation of gluconeogenesis / phagocytosis / energy homeostasis / cellular response to retinoic acid / positive regulation of insulin receptor signaling pathway / positive regulation of T cell proliferation / positive regulation of tyrosine phosphorylation of STAT protein / positive regulation of interleukin-12 production / cholesterol metabolic process / negative regulation of autophagy / response to activity / positive regulation of interleukin-8 production / gluconeogenesis / determination of adult lifespan / female pregnancy / positive regulation of receptor signaling pathway via JAK-STAT / regulation of protein phosphorylation / response to insulin / placenta development Similarity search - Function | |||||||||
Biological species | Mus musculus (house mouse) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 4.5 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_27433.map.gz | 109.3 MB | EMDB map data format | |
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Header (meta data) | emd-27433-v30.xml emd-27433.xml | 14.9 KB 14.9 KB | Display Display | EMDB header |
Images | emd_27433.png | 34.5 KB | ||
Masks | emd_27433_msk_1.map | 125 MB | Mask map | |
Others | emd_27433_half_map_1.map.gz emd_27433_half_map_2.map.gz | 115.9 MB 115.9 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-27433 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-27433 | HTTPS FTP |
-Validation report
Summary document | emd_27433_validation.pdf.gz | 1.1 MB | Display | EMDB validaton report |
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Full document | emd_27433_full_validation.pdf.gz | 1.1 MB | Display | |
Data in XML | emd_27433_validation.xml.gz | 13.7 KB | Display | |
Data in CIF | emd_27433_validation.cif.gz | 16.2 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-27433 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-27433 | HTTPS FTP |
-Related structure data
Related structure data | 8dh9MC 8dh8C 8dhaC 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_27433.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-D3-D7 | ||||||||||||||||||||
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_27433_msk_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: Leptin-bound leptin receptor complex-D3-D7
File | emd_27433_half_map_1.map | ||||||||||||
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Annotation | Leptin-bound leptin receptor complex-D3-D7 | ||||||||||||
Projections & Slices |
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Density Histograms |
-Half map: Leptin-bound leptin receptor complex-D3-D7
File | emd_27433_half_map_2.map | ||||||||||||
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Annotation | Leptin-bound leptin receptor complex-D3-D7 | ||||||||||||
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 / Chimera: Yes / Parent: 0 / Macromolecule list: all |
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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: 63.674754 KDa |
Recombinant expression | Organism: Homo sapiens (human) |
Sequence | String: TQDVVYFPPK ILTSVGSNAS FHCIYKNENQ IISSKQIVWW RNLAEKIPEI QYSIVSDRVS KVTFSNLKAT RPRGKFTYDA VYCCNEQAC HHRYAELYVI DVNINISCET DGYLTKMTCR WSPSTIQSLV GSTVQLRYHR RSLYCPDSPS IHPTSEPKNC V LQRDGFYE ...String: TQDVVYFPPK ILTSVGSNAS FHCIYKNENQ IISSKQIVWW RNLAEKIPEI QYSIVSDRVS KVTFSNLKAT RPRGKFTYDA VYCCNEQAC HHRYAELYVI DVNINISCET DGYLTKMTCR WSPSTIQSLV GSTVQLRYHR RSLYCPDSPS IHPTSEPKNC V LQRDGFYE CVFQPIFLLS GYTMWIRINH SLGSLDSPPT CVLPDSVVKP LPPSNVKAEI TVNTGLLKVS WEKPVFPENN LQ FQIRYGL SGKEIQWKTH EVFDAKSKSA SLLVSDLCAV YVVQVRCRRL DGLGYWSNWS SPAYTLVMDV KVPMRGPEFW RKM DGDVTK KERNVTLLWK PLTKNDSLCS VRRYVVKHRT AHNGTWSEDV GNRTNLTFLW TEPAHTVTVL AVNSLGASLV NFNL TFSWP MSKVSAVESL SAYPLSSSCV ILSWTLSPDD YSLLYLVIEW KILNEDDGMK WLRIPSNVKK FYIHDNFIPI EKYQF SLYP VFMEGVGKPK IINGFTKDAI DKQQNDAGGS GGMKQLEDKV EELLSKNYHL ENEVARLKKL VGERSGGHHH HHH |
-Macromolecule #2: Leptin
Macromolecule | Name: Leptin / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO |
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Source (natural) | Organism: Mus musculus (house mouse) |
Molecular weight | Theoretical: 18.724555 KDa |
Recombinant expression | Organism: Homo sapiens (human) |
Sequence | String: MCWRPLCRFL WLWSYLSYVQ AVPIQKVQDD TKTLIKTIVT RINDISHTQS VSAKQRVTGL DFIPGLHPIL SLSKMDQTLA VYQQVLTSL PSQNVLQIAN DLENLRDLLH LLAFSKSCSL PQTSGLQKPE SLDGVLEASL YSTEVVALSR LQGSLQDILQ Q LDVSPEC |
-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 |
-Image processing
Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 4.5 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 137338 |
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Initial angle assignment | Type: OTHER |
Final angle assignment | Type: OTHER |