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- PDB-6wxj: CSF1R signaling is a regulator of pathogenesis in progressive MS -

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Basic information

Entry
Database: PDB / ID: 6wxj
TitleCSF1R signaling is a regulator of pathogenesis in progressive MS
ComponentsMacrophage colony-stimulating factor 1 receptor
KeywordsTRANSFERASE / CSF1R / inhibitor / TKI / MS
Function / homology
Function and homology information


macrophage colony-stimulating factor receptor activity / forebrain neuron differentiation / CSF1-CSF1R complex / macrophage colony-stimulating factor signaling pathway / cell-cell junction maintenance / regulation of macrophage migration / cellular response to macrophage colony-stimulating factor stimulus / microglial cell proliferation / olfactory bulb development / mammary gland duct morphogenesis ...macrophage colony-stimulating factor receptor activity / forebrain neuron differentiation / CSF1-CSF1R complex / macrophage colony-stimulating factor signaling pathway / cell-cell junction maintenance / regulation of macrophage migration / cellular response to macrophage colony-stimulating factor stimulus / microglial cell proliferation / olfactory bulb development / mammary gland duct morphogenesis / positive regulation by host of viral process / ruffle organization / positive regulation of macrophage proliferation / regulation of bone resorption / positive regulation of cell motility / Other interleukin signaling / positive regulation of macrophage chemotaxis / cytokine binding / growth factor binding / cellular response to cytokine stimulus / monocyte differentiation / regulation of MAPK cascade / macrophage differentiation / hemopoiesis / positive regulation of protein tyrosine kinase activity / Transcriptional Regulation by VENTX / positive regulation of chemokine production / positive regulation of tyrosine phosphorylation of STAT protein / cell surface receptor protein tyrosine kinase signaling pathway / osteoclast differentiation / response to ischemia / regulation of actin cytoskeleton organization / axon guidance / receptor protein-tyrosine kinase / cytokine-mediated signaling pathway / peptidyl-tyrosine phosphorylation / Signaling by CSF1 (M-CSF) in myeloid cells / regulation of cell shape / protein phosphatase binding / protein tyrosine kinase activity / cell population proliferation / protein autophosphorylation / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of ERK1 and ERK2 cascade / receptor complex / positive regulation of cell migration / inflammatory response / positive regulation of protein phosphorylation / negative regulation of cell population proliferation / intracellular membrane-bounded organelle / innate immune response / positive regulation of cell population proliferation / negative regulation of apoptotic process / cell surface / signal transduction / protein homodimerization activity / nucleoplasm / ATP binding / plasma membrane
Similarity search - Function
Macrophage colony-stimulating factor 1 receptor / Tyrosine-protein kinase, receptor class III, conserved site / Receptor tyrosine kinase class III signature. / Immunoglobulin / Immunoglobulin domain / Immunoglobulin domain / Immunoglobulin subtype 2 / Immunoglobulin C-2 Type / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain ...Macrophage colony-stimulating factor 1 receptor / Tyrosine-protein kinase, receptor class III, conserved site / Receptor tyrosine kinase class III signature. / 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
Chem-UF4 / Macrophage colony-stimulating factor 1 receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.62 Å
AuthorsLiu, J.
CitationJournal: Cell Death Dis / Year: 2020
Title: CSF1R signaling is a regulator of pathogenesis in progressive MS.
Authors: Hagan, N. / Kane, J.L. / Grover, D. / Woodworth, L. / Madore, C. / Saleh, J. / Sancho, J. / Liu, J. / Li, Y. / Proto, J. / Zelic, M. / Mahan, A. / Kothe, M. / Scholte, A.A. / Fitzgerald, M. ...Authors: Hagan, N. / Kane, J.L. / Grover, D. / Woodworth, L. / Madore, C. / Saleh, J. / Sancho, J. / Liu, J. / Li, Y. / Proto, J. / Zelic, M. / Mahan, A. / Kothe, M. / Scholte, A.A. / Fitzgerald, M. / Gisevius, B. / Haghikia, A. / Butovsky, O. / Ofengeim, D.
History
DepositionMay 10, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 10, 2021Provider: repository / Type: Initial release
Revision 1.1Oct 18, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Macrophage colony-stimulating factor 1 receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,1792
Polymers37,7231
Non-polymers4561
Water61334
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)80.520, 80.520, 144.060
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number146
Space group name H-MH3

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Components

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


Mass: 37723.090 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CSF1R, FMS / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P07333, receptor protein-tyrosine kinase
#2: Chemical ChemComp-UF4 / 4-(3-{[(2S)-2-(6-methoxypyridin-3-yl)-2,3-dihydro-1,4-benzodioxin-6-yl]methyl}-3H-imidazo[4,5-b]pyridin-6-yl)-2-methylbut-3-yn-2-amine


Mass: 455.508 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H25N5O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 34 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.37 Å3/Da / Density % sol: 48.2 %
Crystal growTemperature: 294 K / Method: vapor diffusion
Details: 0.1 M MES, pH 6.5, 21.3% polyethylene glycol 3350 and 0.25 M ammonium sulfate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X17B1 / Wavelength: 0.9201 Å
DetectorType: DECTRIS EIGER2 X 9M / Detector: PIXEL / Date: Nov 14, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9201 Å / Relative weight: 1
ReflectionResolution: 2.62→48.02 Å / Num. obs: 10436 / % possible obs: 99.5 % / Redundancy: 5.9 % / Rmerge(I) obs: 0.1 / Net I/σ(I): 13.6
Reflection shellResolution: 2.62→2.69 Å / Rmerge(I) obs: 1.1 / Num. unique obs: 10436

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Processing

Software
NameVersionClassification
REFMAC5.8.0257refinement
XDSdata reduction
Aimlessdata scaling
PDB_EXTRACT3.25data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3DPK

3dpk


Resolution: 2.62→48.02 Å / Cor.coef. Fo:Fc: 0.97 / Cor.coef. Fo:Fc free: 0.926 / SU B: 34.744 / SU ML: 0.321 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.851 / ESU R Free: 0.35 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2723 518 5 %RANDOM
Rwork0.1807 ---
obs0.1847 9914 99.52 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 211.75 Å2 / Biso mean: 91.328 Å2 / Biso min: 46.27 Å2
Baniso -1Baniso -2Baniso -3
1--0.75 Å2-0.38 Å20 Å2
2---0.75 Å20 Å2
3---2.44 Å2
Refinement stepCycle: final / Resolution: 2.62→48.02 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2221 0 34 34 2289
Biso mean--84.27 82.01 -
Num. residues----282
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0132315
X-RAY DIFFRACTIONr_bond_other_d0.0020.0172129
X-RAY DIFFRACTIONr_angle_refined_deg1.9211.6563134
X-RAY DIFFRACTIONr_angle_other_deg1.3021.5934940
X-RAY DIFFRACTIONr_dihedral_angle_1_deg8.0945278
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.70323.604111
X-RAY DIFFRACTIONr_dihedral_angle_3_deg20.1915384
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.663158
X-RAY DIFFRACTIONr_chiral_restr0.0810.2290
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.022551
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02480
LS refinement shellResolution: 2.621→2.688 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.309 21 -
Rwork0.371 776 -
all-797 -
obs--99.87 %
Refinement TLS params.Method: refined / Origin x: 9.2498 Å / Origin y: 24.5645 Å / Origin z: 2.848 Å
111213212223313233
T0.0455 Å20.0185 Å2-0.0358 Å2-0.1239 Å2-0.0181 Å2--0.3739 Å2
L3.8007 °2-1.0979 °2-0.7676 °2-1.5886 °20.4882 °2--0.2376 °2
S-0.0858 Å °0.5489 Å °-0.1854 Å °0.2598 Å °0.0117 Å °-0.1232 Å °0.0637 Å °-0.0878 Å °0.0741 Å °

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