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- PDB-4wrm: Structure of the human CSF-1:CSF-1R complex -

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Basic information

Entry
Database: PDB / ID: 4wrm
TitleStructure of the human CSF-1:CSF-1R complex
Components
  • Macrophage colony-stimulating factor 1
  • Macrophage colony-stimulating factor 1 receptor
KeywordsCYTOKINE/CYTOKINE RECEPTOR / cytokine-cytokine receptor complex
Function / homology
Function and homology information


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
Macrophage colony stimulating factor-1 / Macrophage colony stimulating factor-1 (CSF-1) / Macrophage colony-stimulating factor 1 receptor / Tyrosine-protein kinase, receptor class III, conserved site / Receptor tyrosine kinase class III signature. / Four-helical cytokine-like, core / Immunoglobulin / Immunoglobulin domain / Immunoglobulin domain / Immunoglobulin subtype 2 ...Macrophage colony stimulating factor-1 / Macrophage colony stimulating factor-1 (CSF-1) / Macrophage colony-stimulating factor 1 receptor / Tyrosine-protein kinase, receptor class III, conserved site / Receptor tyrosine kinase class III signature. / Four-helical cytokine-like, core / Immunoglobulin / Immunoglobulin domain / Immunoglobulin domain / Immunoglobulin subtype 2 / Immunoglobulin C-2 Type / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / Immunoglobulin subtype / Immunoglobulin / Tyrosine-protein kinase, active site / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / Ig-like domain profile. / Immunoglobulin-like domain / Immunoglobulin-like domain superfamily / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Immunoglobulin-like fold / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Macrophage colony-stimulating factor 1 receptor / Macrophage colony-stimulating factor 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 6.853 Å
AuthorsFelix, J. / De Munck, S. / Elegheert, J. / Savvides, S.N.
CitationJournal: Structure / Year: 2015
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.
History
DepositionOct 24, 2014Deposition site: RCSB / Processing site: PDBE
Revision 1.0Aug 12, 2015Provider: repository / Type: Initial release
Revision 1.1Sep 9, 2015Group: Database references
Revision 1.2Feb 20, 2019Group: Advisory / Data collection / Derived calculations
Category: pdbx_data_processing_status / pdbx_validate_close_contact ...pdbx_data_processing_status / pdbx_validate_close_contact / pdbx_validate_symm_contact / struct_conn / struct_conn_type
Revision 1.3Apr 3, 2019Group: Data collection / Source and taxonomy / Category: entity_src_gen / Item: _entity_src_gen.pdbx_host_org_cell_line
Revision 1.4Jan 10, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_seq_id / _struct_conn.ptnr2_symmetry

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Macrophage colony-stimulating factor 1 receptor
B: Macrophage colony-stimulating factor 1


Theoretical massNumber of molelcules
Total (without water)74,4792
Polymers74,4792
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1940 Å2
ΔGint-1 kcal/mol
Surface area31230 Å2
MethodPISA
Unit cell
Length a, b, c (Å)281.470, 281.470, 91.170
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number178
Space group name H-MP6122

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Components

#1: Protein Macrophage colony-stimulating factor 1 receptor / CSF-1 receptor / M-CSF-R / Proto-oncogene c-Fms


Mass: 54721.512 Da / Num. of mol.: 1 / Fragment: UNP RESIDUES 20-504
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CSF1R, FMS / Cell line (production host): HEK293T / Production host: Homo sapiens (human)
References: UniProt: P07333, receptor protein-tyrosine kinase
#2: Protein Macrophage colony-stimulating factor 1 / MCSF / Lanimostim


Mass: 19757.314 Da / Num. of mol.: 1 / Fragment: UNP RESIDUES 33-181
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CSF1 / Production host: Escherichia coli (E. coli) / References: UniProt: P09603

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 7 Å3/Da / Density % sol: 85 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8 / Details: 0.1 M NaCl, 0.1 M Tris pH 8.0 and 8% w/v PEG 20000

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1.0015 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: Jul 5, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0015 Å / Relative weight: 1
ReflectionResolution: 6.8→48.752 Å / Num. obs: 3953 / % possible obs: 99.5 % / Redundancy: 10.2 % / Biso Wilson estimate: 238.53 Å2 / Rmerge(I) obs: 0.071 / Net I/σ(I): 21.33
Reflection shellResolution: 6.8→7.21 Å / Redundancy: 10.4 % / Rmerge(I) obs: 1.02 / Mean I/σ(I) obs: 2.98 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX(phenix.refine: 1.9_1685)refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4WRL and 4LIQ

4wrl

4liq


Resolution: 6.853→48.752 Å / SU ML: 1.13 / Cross valid method: FREE R-VALUE / σ(F): 1.37 / Phase error: 39.55 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.3593 311 9.74 %
Rwork0.3263 --
obs0.3299 3194 82.66 %
Solvent computationShrinkage radii: 1.1 Å / VDW probe radii: 1.3 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 313.7 Å2
Refinement stepCycle: LAST / Resolution: 6.853→48.752 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4524 0 0 0 4524
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0084635
X-RAY DIFFRACTIONf_angle_d1.26301
X-RAY DIFFRACTIONf_dihedral_angle_d15.2821641
X-RAY DIFFRACTIONf_chiral_restr0.06718
X-RAY DIFFRACTIONf_plane_restr0.006814
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
6.8533-8.62660.43011120.37541091X-RAY DIFFRACTION65
8.6266-48.75320.33651990.30971792X-RAY DIFFRACTION100
Refinement TLS params.Method: refined / Origin x: -69.5998 Å / Origin y: 163.7688 Å / Origin z: -6.8841 Å
111213212223313233
T2.9341 Å2-0.2475 Å2-0.4947 Å2-2.5904 Å2-1.4313 Å2--2.926 Å2
L0.3858 °20.3954 °20.1659 °2-0.47 °20.0338 °2--1.1419 °2
S-0.5994 Å °-0.3743 Å °0.2151 Å °-0.517 Å °0.3342 Å °-0.5155 Å °-0.0079 Å °0.7508 Å °-1.5123 Å °
Refinement TLS groupSelection details: all

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