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- PDB-7z3p: Crystal structure of the mouse leptin:LepR-CRH2 encounter complex... -
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Open data
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Basic information
Entry | Database: PDB / ID: 7z3p | ||||||
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Title | Crystal structure of the mouse leptin:LepR-CRH2 encounter complex to 1.95 A resolution. | ||||||
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![]() | CYTOKINE / leptin / obesity / leptin receptor / LepR / adipose tissue / hypothalamus / immune system | ||||||
Function / homology | ![]() 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 / prostaglandin secretion / negative regulation of glucose import / 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 / cytokine receptor activity / peptide hormone receptor binding / 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 / female pregnancy / determination of adult lifespan / positive regulation of receptor signaling pathway via JAK-STAT / regulation of protein phosphorylation / response to insulin / placenta development Similarity search - Function | ||||||
Biological species | ![]() ![]() | ||||||
Method | ![]() ![]() ![]() | ||||||
![]() | Tsirigotaki, A. / Verschueren, K. / Savvides, S.N. / Verstraete, K. | ||||||
Funding support | ![]()
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![]() | ![]() Title: Mechanism of receptor assembly via the pleiotropic adipokine Leptin. Authors: Alexandra Tsirigotaki / Ann Dansercoer / Koen H G Verschueren / Iva Marković / Christoph Pollmann / Maximillian Hafer / Jan Felix / Catherine Birck / Wouter Van Putte / Dominiek Catteeuw / ...Authors: Alexandra Tsirigotaki / Ann Dansercoer / Koen H G Verschueren / Iva Marković / Christoph Pollmann / Maximillian Hafer / Jan Felix / Catherine Birck / Wouter Van Putte / Dominiek Catteeuw / Jan Tavernier / J Fernando Bazan / Jacob Piehler / Savvas N Savvides / Kenneth Verstraete / ![]() ![]() ![]() ![]() Abstract: The adipokine Leptin activates its receptor LEP-R in the hypothalamus to regulate body weight and exerts additional pleiotropic functions in immunity, fertility and cancer. However, the structure and ...The adipokine Leptin activates its receptor LEP-R in the hypothalamus to regulate body weight and exerts additional pleiotropic functions in immunity, fertility and cancer. However, the structure and mechanism of Leptin-mediated LEP-R assemblies has remained unclear. Intriguingly, the signaling-competent isoform of LEP-R is only lowly abundant amid several inactive short LEP-R isoforms contributing to a mechanistic conundrum. Here we show by X-ray crystallography and cryo-EM that, in contrast to long-standing paradigms, Leptin induces type I cytokine receptor assemblies featuring 3:3 stoichiometry and demonstrate such Leptin-induced trimerization of LEP-R on living cells via single-molecule microscopy. In mediating these assemblies, Leptin undergoes drastic restructuring that activates its site III for binding to the Ig domain of an adjacent LEP-R. These interactions are abolished by mutations linked to obesity. Collectively, our study provides the structural and mechanistic framework for how evolutionarily conserved Leptin:LEP-R assemblies with 3:3 stoichiometry can engage distinct LEP-R isoforms to achieve signaling. | ||||||
History |
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Structure visualization
Structure viewer | Molecule: ![]() ![]() |
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Downloads & links
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Download
PDBx/mmCIF format | ![]() | 148.3 KB | Display | ![]() |
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PDB format | ![]() | 114.4 KB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
Others | ![]() |
-Validation report
Summary document | ![]() | 455.6 KB | Display | ![]() |
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Full document | ![]() | 459.3 KB | Display | |
Data in XML | ![]() | 14.7 KB | Display | |
Data in CIF | ![]() | 20.7 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 7z3qC ![]() 7z3rC ![]() 8av2C ![]() 8avbC ![]() 8avcC ![]() 8avdC ![]() 8aveC ![]() 8avfC ![]() 8avoC ![]() 8b7qC ![]() 1ax8S ![]() 3v6oS S: Starting model for refinement C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
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Assembly
Deposited unit | ![]()
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Unit cell |
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Components
#1: Protein | Mass: 17340.684 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Details: Mouse leptin:CRH2 complex was produced in HEK293 FreeStyle cells in the presence of kifunensine. Source: (gene. exp.) ![]() ![]() ![]() |
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#2: Protein | Mass: 26038.537 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Details: Prior the crystallisation, the N-terminal His-tag was removed by a proteolytic digest with TEV protease. Source: (gene. exp.) ![]() ![]() ![]() |
#3: Chemical | ChemComp-CA / |
#4: Chemical | ChemComp-PEG / |
#5: Water | ChemComp-HOH / |
Has ligand of interest | N |
-Experimental details
-Experiment
Experiment | Method: ![]() |
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Sample preparation
Crystal | Density Matthews: 2.62 Å3/Da / Density % sol: 53.08 % |
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Crystal grow | Temperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8 Details: BCS screen, condition H1 0.04 M Calcium chloride dihydrate 0.04 M sodium formate 0.1 M Tris pH 8.0 25% PEG Smear Low cryo: 20 % PEG 400 Temp details: Temperature-controlled cabinet |
-Data collection
Diffraction | Mean temperature: 100 K / Ambient temp details: cold nitrogen gas stream / Serial crystal experiment: N |
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Diffraction source | Source: ![]() ![]() ![]() |
Detector | Type: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Feb 1, 2020 / Details: HPM and KB mirrors |
Radiation | Monochromator: Si[111] monochromator / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray |
Radiation wavelength | Wavelength: 0.98011 Å / Relative weight: 1 |
Reflection | Resolution: 1.94→46.35 Å / Num. obs: 34115 / % possible obs: 99.2 % / Redundancy: 13.2 % / Biso Wilson estimate: 44.417 Å2 / CC1/2: 0.999 / Rrim(I) all: 0.127 / Net I/σ(I): 16.08 |
Reflection shell | Resolution: 1.94→1.99 Å / Mean I/σ(I) obs: 0.8 / Num. unique obs: 2017 / CC1/2: 0.346 / Rrim(I) all: 3.271 / % possible all: 88.9 |
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Processing
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Refinement | Method to determine structure: ![]() Starting model: 1ax8, 3v6o Resolution: 1.943→46.35 Å / Cor.coef. Fo:Fc: 0.947 / Cor.coef. Fo:Fc free: 0.935 / SU R Cruickshank DPI: 0.125 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.128 / SU Rfree Blow DPI: 0.121 / SU Rfree Cruickshank DPI: 0.12
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Displacement parameters | Biso mean: 54.97 Å2
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Refine analyze | Luzzati coordinate error obs: 0.27 Å | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Refinement step | Cycle: LAST / Resolution: 1.943→46.35 Å
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Refine LS restraints |
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LS refinement shell | Resolution: 1.943→1.96 Å
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Refinement TLS params. | Refine-ID: X-RAY DIFFRACTION
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Refinement TLS group |
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