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Basic information
Entry | Database: PDB / ID: 4wrl | |||||||||
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Title | Structure of the human CSF-1:CSF-1R complex | |||||||||
![]() | (Macrophage colony-stimulating factor ...) x 2 | |||||||||
![]() | CYTOKINE/CYTOKINE RECEPTOR / cytokine-cytokine receptor complex | |||||||||
Function / homology | ![]() regulation of macrophage derived foam cell differentiation / mammary gland fat development / positive regulation of macrophage colony-stimulating factor signaling pathway / macrophage homeostasis / monocyte activation / macrophage colony-stimulating factor receptor binding / monocyte homeostasis / osteoclast proliferation / positive regulation of macrophage migration / developmental process involved in reproduction ...regulation of macrophage derived foam cell differentiation / mammary gland fat development / positive regulation of macrophage colony-stimulating factor signaling pathway / macrophage homeostasis / monocyte activation / macrophage colony-stimulating factor receptor binding / monocyte homeostasis / osteoclast proliferation / positive regulation of macrophage migration / developmental process involved in reproduction / positive regulation of odontogenesis of dentin-containing tooth / macrophage colony-stimulating factor receptor activity / forebrain neuron differentiation / CSF1-CSF1R complex / macrophage colony-stimulating factor signaling pathway / cell-cell junction maintenance / positive regulation of microglial cell migration / regulation of macrophage migration / mammary duct terminal end bud growth / cellular response to macrophage colony-stimulating factor stimulus / microglial cell proliferation / positive regulation of macrophage differentiation / positive regulation of macrophage derived foam cell differentiation / positive regulation of mononuclear cell proliferation / olfactory bulb development / myeloid leukocyte migration / mammary gland duct morphogenesis / positive regulation by host of viral process / neutrophil homeostasis / positive regulation of multicellular organism growth / ruffle organization / positive regulation of monocyte differentiation / positive regulation of osteoclast differentiation / positive regulation of macrophage proliferation / positive regulation of Ras protein signal transduction / regulation of bone resorption / positive regulation of cell motility / branching involved in mammary gland duct morphogenesis / positive regulation of cell-matrix adhesion / Other interleukin signaling / positive regulation of macrophage chemotaxis / cytokine binding / growth factor binding / cellular response to cytokine stimulus / Interleukin-10 signaling / monocyte differentiation / regulation of MAPK cascade / macrophage differentiation / hemopoiesis / positive regulation of protein tyrosine kinase activity / Transcriptional Regulation by VENTX / regulation of ossification / positive regulation of protein kinase activity / positive regulation of chemokine production / positive regulation of tyrosine phosphorylation of STAT protein / homeostasis of number of cells within a tissue / cell surface receptor protein tyrosine kinase signaling pathway / positive regulation of protein metabolic process / osteoclast differentiation / cytokine activity / response to ischemia / regulation of actin cytoskeleton organization / Post-translational protein phosphorylation / axon guidance / growth factor activity / receptor protein-tyrosine kinase / cytokine-mediated signaling pathway / peptidyl-tyrosine phosphorylation / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / Signaling by CSF1 (M-CSF) in myeloid cells / regulation of cell shape / protein phosphatase binding / protein tyrosine kinase activity / cell population proliferation / Ras protein signal transduction / protein autophosphorylation / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of ERK1 and ERK2 cascade / receptor complex / nuclear body / positive regulation of cell migration / inflammatory response / positive regulation of protein phosphorylation / negative regulation of cell population proliferation / endoplasmic reticulum lumen / intracellular membrane-bounded organelle / innate immune response / positive regulation of cell population proliferation / positive regulation of gene expression / negative regulation of apoptotic process / perinuclear region of cytoplasm / cell surface / signal transduction / protein homodimerization activity / extracellular space / extracellular region / nucleoplasm / ATP binding / identical protein binding / membrane Similarity search - Function | |||||||||
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Method | ![]() ![]() ![]() | |||||||||
![]() | Felix, J. / De Munck, S. / Elegheert, J. / Savvides, S.N. | |||||||||
![]() | ![]() Title: Structure and Assembly Mechanism of the Signaling Complex Mediated by Human CSF-1. Authors: Jan Felix / Steven De Munck / Kenneth Verstraete / Leander Meuris / Nico Callewaert / Jonathan Elegheert / Savvas N Savvides / ![]() Abstract: Human colony-stimulating factor 1 receptor (hCSF-1R) is unique among the hematopoietic receptors because it is activated by two distinct cytokines, CSF-1 and interleukin-34 (IL-34). Despite ever- ...Human colony-stimulating factor 1 receptor (hCSF-1R) is unique among the hematopoietic receptors because it is activated by two distinct cytokines, CSF-1 and interleukin-34 (IL-34). Despite ever-growing insights into the central role of hCSF-1R signaling in innate and adaptive immunity, inflammatory diseases, and cancer, the structural basis of the functional dichotomy of hCSF-1R has remained elusive. Here, we report crystal structures of ternary complexes between hCSF-1 and hCSF-1R, including their complete extracellular assembly, and propose a mechanism for the cooperative human CSF-1:CSF-1R complex that relies on the adoption by dimeric hCSF-1 of an active conformational state and homotypic receptor interactions. Furthermore, we trace the cytokine-binding duality of hCSF-1R to a limited set of conserved interactions mediated by functionally equivalent residues on CSF-1 and IL-34 that play into the geometric requirements of hCSF-1R activation, and map the possible mechanistic consequences of somatic mutations in hCSF-1R associated with cancer. | |||||||||
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Structure visualization
Structure viewer | Molecule: ![]() ![]() |
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Downloads & links
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PDBx/mmCIF format | ![]() | 358.3 KB | Display | ![]() |
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PDB format | ![]() | 294.8 KB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
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-Validation report
Summary document | ![]() | 2.4 MB | Display | ![]() |
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Full document | ![]() | 2.4 MB | Display | |
Data in XML | ![]() | 32.7 KB | Display | |
Data in CIF | ![]() | 42.5 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 4wrmC ![]() 3uf2S ![]() 4dkdS S: Starting model for refinement C: citing same article ( |
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Similar structure data |
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Assembly
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Components
-Macrophage colony-stimulating factor ... , 2 types, 4 molecules ACBD
#1: Protein | Mass: 31583.867 Da / Num. of mol.: 2 / Fragment: UNP residues 20-296 / Mutation: N240Q Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() References: UniProt: P07333, receptor protein-tyrosine kinase #2: Protein | Mass: 19757.314 Da / Num. of mol.: 2 / Fragment: UNP residues 33-181 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() |
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-Sugars , 5 types, 9 molecules ![](data/chem/img/SIA.gif)
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#3: Polysaccharide | #4: Polysaccharide | beta-D-galactopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose | Source method: isolated from a genetically manipulated source #5: Polysaccharide | #6: Sugar | ChemComp-SIA / | #7: Sugar | |
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-Experimental details
-Experiment
Experiment | Method: ![]() |
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Sample preparation
Crystal | Density Matthews: 3.44 Å3/Da / Density % sol: 64.28 % |
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Crystal grow | Temperature: 293 K / Method: vapor diffusion, hanging drop / pH: 8.5 Details: 0.2 M Lithium sulfate monohydrate, 0.1 M Tris pH 8.5 and 28% w/v PEG 3350 |
-Data collection
Diffraction | Mean temperature: 100 K |
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Diffraction source | Source: ![]() ![]() ![]() |
Detector | Type: PSI PILATUS 6M / Detector: PIXEL / Date: Apr 25, 2014 |
Radiation | Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray |
Radiation wavelength | Wavelength: 0.97625 Å / Relative weight: 1 |
Reflection | Resolution: 2.8→49.71 Å / Num. obs: 34125 / % possible obs: 99.8 % / Redundancy: 6.9 % / Biso Wilson estimate: 82.26 Å2 / Rmerge(I) obs: 0.064 / Net I/σ(I): 20.73 |
Reflection shell | Resolution: 2.8→2.97 Å / Redundancy: 6.8 % / Rmerge(I) obs: 0.815 / Mean I/σ(I) obs: 2.32 / % possible all: 99.2 |
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Processing
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Refinement | Method to determine structure: ![]() Starting model: 4DKD, 3UF2 Resolution: 2.802→49.71 Å / SU ML: 0.52 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 30.59 / Stereochemistry target values: ML Details: Galactose 403 and Galactose 408 on chain C failed to be fitted in the exo-anomeric conformation of their glycosidic bond
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Solvent computation | Shrinkage radii: 1 Å / VDW probe radii: 1.2 Å / Solvent model: FLAT BULK SOLVENT MODEL | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Refinement step | Cycle: LAST / Resolution: 2.802→49.71 Å
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Refine LS restraints |
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LS refinement shell |
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Refinement TLS params. | Method: refined / Refine-ID: X-RAY DIFFRACTION
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Refinement TLS group |
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