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Open data
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Basic information
Entry | Database: PDB / ID: 7ysw | ||||||
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Title | Cryo-EM Structure of FGF23-FGFR4-aKlotho-HS Quaternary Complex | ||||||
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![]() | SIGNALING PROTEIN / FGF hormones / FGF Receptor / Klotho Co-Receptor / Heparan Sulfate Glycosaminoglycans | ||||||
Function / homology | ![]() type 1 fibroblast growth factor receptor binding / FGFRL1 modulation of FGFR1 signaling / norepinephrine biosynthetic process / FGFR4 mutant receptor activation / betaKlotho-mediated ligand binding / positive regulation of vitamin D 24-hydroxylase activity / beta-glucuronidase / negative regulation of hormone secretion / FGFR1c and Klotho ligand binding and activation / beta-glucuronidase activity ...type 1 fibroblast growth factor receptor binding / FGFRL1 modulation of FGFR1 signaling / norepinephrine biosynthetic process / FGFR4 mutant receptor activation / betaKlotho-mediated ligand binding / positive regulation of vitamin D 24-hydroxylase activity / beta-glucuronidase / negative regulation of hormone secretion / FGFR1c and Klotho ligand binding and activation / beta-glucuronidase activity / regulation of phosphate transport / positive regulation of MAPKKK cascade by fibroblast growth factor receptor signaling pathway / intracellular phosphate ion homeostasis / regulation of extracellular matrix disassembly / vitamin D catabolic process / response to sodium phosphate / negative regulation of bone mineralization / phosphate ion homeostasis / Signaling by activated point mutants of FGFR3 / FGFR3c ligand binding and activation / Phospholipase C-mediated cascade; FGFR3 / regulation of bile acid biosynthetic process / fibroblast growth factor receptor binding / cellular response to vitamin D / FGFR2c ligand binding and activation / Activated point mutants of FGFR2 / Phospholipase C-mediated cascade; FGFR2 / vitamin D binding / FGFR4 ligand binding and activation / fibroblast growth factor receptor activity / Phospholipase C-mediated cascade; FGFR4 / Signaling by activated point mutants of FGFR1 / FGFR1c ligand binding and activation / energy reserve metabolic process / Downstream signaling of activated FGFR1 / Phospholipase C-mediated cascade: FGFR1 / response to vitamin D / cellular response to leptin stimulus / cellular response to interleukin-6 / negative regulation of systemic arterial blood pressure / response to angiotensin / cellular response to parathyroid hormone stimulus / positive regulation of catalytic activity / beta-glucosidase activity / positive regulation of DNA biosynthetic process / negative regulation of osteoblast differentiation / PI-3K cascade:FGFR3 / PI-3K cascade:FGFR2 / fibroblast growth factor binding / PI-3K cascade:FGFR4 / PI-3K cascade:FGFR1 / positive regulation of proteolysis / response to magnesium ion / regulation of lipid metabolic process / PI3K Cascade / fibroblast growth factor receptor signaling pathway / positive regulation of bone mineralization / SHC-mediated cascade:FGFR3 / SHC-mediated cascade:FGFR2 / calcium ion homeostasis / SHC-mediated cascade:FGFR4 / Signaling by FGFR4 in disease / SHC-mediated cascade:FGFR1 / FRS-mediated FGFR3 signaling / FRS-mediated FGFR2 signaling / transport vesicle / Signaling by FGFR3 in disease / FRS-mediated FGFR4 signaling / FRS-mediated FGFR1 signaling / Signaling by FGFR2 in disease / ERK1 and ERK2 cascade / Signaling by FGFR1 in disease / regulation of cell migration / response to activity / cholesterol homeostasis / determination of adult lifespan / receptor protein-tyrosine kinase / Negative regulation of FGFR3 signaling / animal organ morphogenesis / Negative regulation of FGFR2 signaling / Post-translational protein phosphorylation / Negative regulation of FGFR4 signaling / Negative regulation of FGFR1 signaling / growth factor activity / peptidyl-tyrosine phosphorylation / hormone activity / Constitutive Signaling by Aberrant PI3K in Cancer / Golgi lumen / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / PIP3 activates AKT signaling / glucose homeostasis / cell migration / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / heparin binding / RAF/MAP kinase cascade / protein autophosphorylation / receptor complex / positive regulation of ERK1 and ERK2 cascade / positive regulation of MAPK cascade / endosome Similarity search - Function | ||||||
Biological species | ![]() | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.03 Å | ||||||
![]() | Mohammadi, M. / Chen, L. | ||||||
Funding support | ![]()
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![]() | ![]() Title: Structural basis for FGF hormone signalling. Authors: Lingfeng Chen / Lili Fu / Jingchuan Sun / Zhiqiang Huang / Mingzhen Fang / Allen Zinkle / Xin Liu / Junliang Lu / Zixiang Pan / Yang Wang / Guang Liang / Xiaokun Li / Gaozhi Chen / Moosa Mohammadi / ![]() ![]() Abstract: α/βKlotho coreceptors simultaneously engage fibroblast growth factor (FGF) hormones (FGF19, FGF21 and FGF23) and their cognate cell-surface FGF receptors (FGFR1-4) thereby stabilizing the endocrine ...α/βKlotho coreceptors simultaneously engage fibroblast growth factor (FGF) hormones (FGF19, FGF21 and FGF23) and their cognate cell-surface FGF receptors (FGFR1-4) thereby stabilizing the endocrine FGF-FGFR complex. However, these hormones still require heparan sulfate (HS) proteoglycan as an additional coreceptor to induce FGFR dimerization/activation and hence elicit their essential metabolic activities. To reveal the molecular mechanism underpinning the coreceptor role of HS, we solved cryo-electron microscopy structures of three distinct 1:2:1:1 FGF23-FGFR-αKlotho-HS quaternary complexes featuring the 'c' splice isoforms of FGFR1 (FGFR1c), FGFR3 (FGFR3c) or FGFR4 as the receptor component. These structures, supported by cell-based receptor complementation and heterodimerization experiments, reveal that a single HS chain enables FGF23 and its primary FGFR within a 1:1:1 FGF23-FGFR-αKlotho ternary complex to jointly recruit a lone secondary FGFR molecule leading to asymmetric receptor dimerization and activation. However, αKlotho does not directly participate in recruiting the secondary receptor/dimerization. We also show that the asymmetric mode of receptor dimerization is applicable to paracrine FGFs that signal solely in an HS-dependent fashion. Our structural and biochemical data overturn the current symmetric FGFR dimerization paradigm and provide blueprints for rational discovery of modulators of FGF signalling as therapeutics for human metabolic diseases and cancer. | ||||||
History |
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Structure visualization
Structure viewer | Molecule: ![]() ![]() |
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Downloads & links
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Download
PDBx/mmCIF format | ![]() | 314.5 KB | Display | ![]() |
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PDB format | ![]() | 253.3 KB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
Others | ![]() |
-Validation report
Arichive directory | ![]() ![]() | HTTPS FTP |
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-Related structure data
Related structure data | ![]() 34084MC ![]() 7yshC ![]() 7ysuC M: map data used to model this data 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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Components
-Fibroblast growth factor ... , 2 types, 3 molecules CEB
#1: Protein | Mass: 23652.729 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() References: UniProt: P22455, receptor protein-tyrosine kinase #3: Protein | | Mass: 20450.064 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() |
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-Protein / Sugars , 2 types, 2 molecules A
#2: Protein | Mass: 108404.914 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() |
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#4: Polysaccharide | 2-deoxy-6-O-sulfo-2-(sulfoamino)-alpha-D-glucopyranose-(1-4)-2-O-sulfo-alpha-L-idopyranuronic acid- ...2-deoxy-6-O-sulfo-2-(sulfoamino)-alpha-D-glucopyranose-(1-4)-2-O-sulfo-alpha-L-idopyranuronic acid-(1-4)-2-deoxy-6-O-sulfo-2-(sulfoamino)-alpha-D-glucopyranose-(1-4)-2-O-sulfo-alpha-L-idopyranuronic acid-(1-4)-2-deoxy-6-O-sulfo-2-(sulfoamino)-alpha-D-glucopyranose-(1-4)-2-O-sulfo-alpha-L-idopyranuronic acid-(1-4)-2-deoxy-6-O-sulfo-2-(sulfoamino)-alpha-D-glucopyranose-(1-4)-2-O-sulfo-alpha-L-idopyranuronic acid-(1-4)-2-deoxy-6-O-sulfo-2-(sulfoamino)-alpha-D-glucopyranose-(1-4)-2-O-sulfo-alpha-L-idopyranuronic acid Type: oligosaccharide / Mass: 2905.368 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source |
-Non-polymers , 2 types, 2 molecules ![](data/chem/img/CU.gif)
![](data/chem/img/ZN.gif)
![](data/chem/img/ZN.gif)
#5: Chemical | ChemComp-CU / |
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#6: Chemical | ChemComp-ZN / |
-Details
Has ligand of interest | Y |
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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 |
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Sample preparation
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Source (natural) | Organism: ![]() | ||||||||||||||||||||||||
Source (recombinant) |
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Buffer solution | pH: 7.5 | ||||||||||||||||||||||||
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES | ||||||||||||||||||||||||
Vitrification | Cryogen name: ETHANE |
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Electron microscopy imaging
Experimental equipment | ![]() Model: Talos Arctica / Image courtesy: FEI Company |
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Microscopy | Model: FEI TALOS ARCTICA |
Electron gun | Electron source: ![]() |
Electron lens | Mode: BRIGHT FIELD / Nominal defocus max: 2800 nm / Nominal defocus min: 700 nm |
Image recording | Electron dose: 53.84 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) |
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Processing
CTF correction | Type: NONE | ||||||||||||||||||||||||
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3D reconstruction | Resolution: 3.03 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 856877 / Symmetry type: POINT | ||||||||||||||||||||||||
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