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- PDB-8w1l: Structure of CSF1R kinase domain in complex with Cpd 32 -

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Basic information

Entry
Database: PDB / ID: 8w1l
TitleStructure of CSF1R kinase domain in complex with Cpd 32
ComponentsMacrophage colony-stimulating factor 1 receptor,CSF1R
KeywordsTRANSFERASE / Inhibitor complex
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
: / Macrophage colony-stimulating factor 1 receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.26 Å
AuthorsKothe, M. / Chodaparambil, J.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Acs Med.Chem.Lett. / Year: 2024
Title: Identification of Selective Imidazopyridine CSF1R Inhibitors.
Authors: Kane Jr., J.L. / Asmussen, G. / Batchelor, J. / Cromwell, M. / Fezoui, M. / Fitzgerald, M. / Giese, B. / Gladysheva, T. / Holley, S. / Keefe, K. / Kothe, M. / Lam, B. / Lim, S. / Liu, J. / ...Authors: Kane Jr., J.L. / Asmussen, G. / Batchelor, J. / Cromwell, M. / Fezoui, M. / Fitzgerald, M. / Giese, B. / Gladysheva, T. / Holley, S. / Keefe, K. / Kothe, M. / Lam, B. / Lim, S. / Liu, J. / Ma, L. / Metz, M. / Scholte, A.A. / Shum, P. / Wei, L. / Woodworth, L. / Edling, A.
History
DepositionFeb 16, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 29, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Macrophage colony-stimulating factor 1 receptor,CSF1R
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,6365
Polymers37,8501
Non-polymers7864
Water1,38777
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)81.020, 81.020, 146.060
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number146
Space group name H-MH3
Space group name HallR3
Symmetry operation#1: x,y,z
#2: -y,x-y,z
#3: -x+y,-x,z
#4: x+1/3,y+2/3,z+2/3
#5: -y+1/3,x-y+2/3,z+2/3
#6: -x+y+1/3,-x+2/3,z+2/3
#7: x+2/3,y+1/3,z+1/3
#8: -y+2/3,x-y+1/3,z+1/3
#9: -x+y+2/3,-x+1/3,z+1/3

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Components

#1: Protein Macrophage colony-stimulating factor 1 receptor,CSF1R / CSF-1 receptor / CSF-1-R / CSF-1R / M-CSF-R / Proto-oncogene c-Fms


Mass: 37850.258 Da / Num. of mol.: 1
Mutation: residues 679-752 replaced by residues 577-597 of FGFR1
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-A1AE3 / [3-({3-methoxy-4-[(6-methoxypyridin-3-yl)methoxy]phenyl}methyl)-3H-imidazo[4,5-b]pyridin-6-yl](2-oxa-6-azaspiro[3.3]heptan-6-yl)methanone


Mass: 501.534 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H27N5O5 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#4: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 77 / 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: 2.44 Å3/Da / Density % sol: 49.54 %
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 6.5
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: APS / Beamline: 22-ID / Wavelength: 1 Å
DetectorType: MAR CCD 300 mm / Detector: CCD / Date: Apr 15, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.26→32.39 Å / Num. obs: 15788 / % possible obs: 94.47 % / Redundancy: 2.5 % / Biso Wilson estimate: 56.01 Å2 / Rsym value: 0.049 / Net I/σ(I): 25.7
Reflection shellResolution: 2.26→2.343 Å / Num. unique obs: 1378 / Rsym value: 0.7 / % possible all: 82.8

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.26→32.39 Å / SU ML: 0.277 / Cross valid method: FREE R-VALUE / σ(F): 0.06 / Phase error: 27.1057
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2255 1583 10.03 %
Rwork0.1723 14205 -
obs0.1776 15788 94.5 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 76.12 Å2
Refinement stepCycle: LAST / Resolution: 2.26→32.39 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2132 0 53 77 2262
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.012239
X-RAY DIFFRACTIONf_angle_d0.97123051
X-RAY DIFFRACTIONf_chiral_restr0.057337
X-RAY DIFFRACTIONf_plane_restr0.0094387
X-RAY DIFFRACTIONf_dihedral_angle_d8.7368318
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.26-2.330.30751270.24391133X-RAY DIFFRACTION82.62
2.33-2.420.29291260.22181191X-RAY DIFFRACTION86.99
2.42-2.510.25151390.20511241X-RAY DIFFRACTION91.27
2.52-2.630.31291360.1951263X-RAY DIFFRACTION92.4
2.63-2.770.27171510.19981320X-RAY DIFFRACTION96.21
2.77-2.940.25631520.20061330X-RAY DIFFRACTION97.82
2.94-3.170.23871460.19341338X-RAY DIFFRACTION97.95
3.17-3.490.24781520.18521372X-RAY DIFFRACTION99.48
3.49-3.990.25841520.17111351X-RAY DIFFRACTION99.6
3.99-5.020.18011550.15121336X-RAY DIFFRACTION98.09
5.03-32.390.19981470.15441330X-RAY DIFFRACTION97.17
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
14.349008433862.589271866610.8685745131555.14912418990.7459445209022.83248706948-0.253140449023-0.3354859378780.528266011267-0.1935377020310.04282873398970.562982687866-0.375591731744-0.1592857598280.22658931060.3860111423640.0190033257986-0.0008799341146440.448536775495-0.007185221003560.426222896219-19.237390016556.19626893736.01367075044
23.15337396334-2.47100360548-4.198327051118.210033268065.236095981796.26035498991-0.7808521306560.476177868176-1.08360844223-0.7136982414140.03086004257541.126607824060.44069518206-1.261671558430.1206717178620.5276543918460.0207925303074-0.3208128976360.8669795577590.1447127470260.864261743027-38.392868070837.9143568472-6.14274212218
37.57641881514.124516041422.821697535835.890346750892.143951890983.79732645927-0.4685960799150.437832051488-0.464420390513-0.8535796190420.541348345745-0.0029170130555-0.138536723622-0.00146402095655-0.03136444527680.559332429984-0.0686199774649-0.04139030613230.525671537716-0.06395799076170.529995611745-26.296963302240.1991667728-6.95571565972
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION / Auth asym-ID: A / Label asym-ID: A

IDRefine TLS-IDSelection detailsAuth seq-IDLabel seq-ID
11chain 'A' and (resid 752 through 914 )752 - 914120 - 282
22chain 'A' and (resid 563 through 584 )563 - 5841 - 22
33chain 'A' and (resid 585 through 751 )585 - 75123 - 119

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