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- PDB-8cgc: Structure of CSF1R in complex with a pyrollopyrimidine (compound 23) -

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Basic information

Entry
Database: PDB / ID: 8cgc
TitleStructure of CSF1R in complex with a pyrollopyrimidine (compound 23)
ComponentsMacrophage colony-stimulating factor 1 receptor
KeywordsLIGASE / Kinase / CSF1R / Inhibitors
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
(2S)-2-hydroxybutanedioic acid / Chem-UIK / Macrophage colony-stimulating factor 1 receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.925 Å
AuthorsAarhus, T.I. / Bjornstad, F. / Wolowczyk, C. / Larsen, K.U. / Rognstad, L. / Leithaug, T. / Unger, A. / Habenberger, P. / Wolff, A. / Bjorkoy, G. ...Aarhus, T.I. / Bjornstad, F. / Wolowczyk, C. / Larsen, K.U. / Rognstad, L. / Leithaug, T. / Unger, A. / Habenberger, P. / Wolff, A. / Bjorkoy, G. / Pridans, C. / Eickhoff, J. / Klebl, B. / Hoff, B.H. / Sundby, E.
Funding support1items
OrganizationGrant numberCountry
Other government
CitationJournal: J.Med.Chem. / Year: 2023
Title: Synthesis and Development of Highly Selective Pyrrolo[2,3- d ]pyrimidine CSF1R Inhibitors Targeting the Autoinhibited Form.
Authors: Aarhus, T.I. / Bjornstad, F. / Wolowczyk, C. / Larsen, K.U. / Rognstad, L. / Leithaug, T. / Unger, A. / Habenberger, P. / Wolf, A. / Bjorkoy, G. / Pridans, C. / Eickhoff, J. / Klebl, B. / Hoff, B.H. / Sundby, E.
History
DepositionFeb 3, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 24, 2023Provider: repository / Type: Initial release
Revision 1.1Jun 7, 2023Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Feb 7, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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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)39,2454
Polymers38,6601
Non-polymers5853
Water6,828379
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area270 Å2
ΔGint-1 kcal/mol
Surface area15040 Å2
Unit cell
Length a, b, c (Å)81.013, 81.013, 143.237
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number146
Space group name H-MH3
Components on special symmetry positions
IDModelComponents
11A-1383-

HOH

21A-1431-

HOH

31A-1447-

HOH

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Components

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


Mass: 38660.320 Da / Num. of mol.: 1 / Mutation: S688A
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-LMR / (2S)-2-hydroxybutanedioic acid / L-Malate


Mass: 134.087 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H6O5
#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-UIK / [4-[4-[methyl-[(3-methylphenyl)methyl]amino]-7~{H}-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]methanol


Mass: 358.436 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H22N4O / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 379 / 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: 2.34 Å3/Da / Density % sol: 47.45 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7 / Details: 0.3 M DL-Malic acid pH 7.0, 23.0% w/v PEG 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID29 / Wavelength: 0.99187 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Mar 6, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99187 Å / Relative weight: 1
ReflectionResolution: 1.925→31.895 Å / Num. obs: 25909 / % possible obs: 97.6 % / Redundancy: 3.6 % / Biso Wilson estimate: 28.1 Å2 / CC1/2: 0.997 / Rmerge(I) obs: 0.061 / Rpim(I) all: 0.036 / Rrim(I) all: 0.071 / Net I/σ(I): 10.7
Reflection shellResolution: 1.925→1.994 Å / Redundancy: 3.3 % / Rmerge(I) obs: 0.451 / Mean I/σ(I) obs: 2.6 / Num. unique obs: 2572 / CC1/2: 0.89 / Rpim(I) all: 0.282 / Rrim(I) all: 0.536 / % possible all: 98.2

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Processing

Software
NameVersionClassification
REFMAC5.8.0403refinement
autoPROCdata reduction
Aimlessdata scaling
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 2i1m

2i1m


Resolution: 1.925→31.895 Å / Cor.coef. Fo:Fc: 0.973 / Cor.coef. Fo:Fc free: 0.95 / SU B: 3.548 / SU ML: 0.101 / Cross valid method: FREE R-VALUE / ESU R: 0.144 / ESU R Free: 0.141
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2059 1231 4.751 %
Rwork0.1516 24678 -
all0.154 --
obs-25909 97.56 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT
Displacement parametersBiso mean: 32.398 Å2
Baniso -1Baniso -2Baniso -3
1--1.17 Å2-0.585 Å20 Å2
2---1.17 Å20 Å2
3---3.797 Å2
Refinement stepCycle: LAST / Resolution: 1.925→31.895 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2462 0 42 379 2883
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0122657
X-RAY DIFFRACTIONr_bond_other_d0.0010.0162497
X-RAY DIFFRACTIONr_angle_refined_deg1.381.6383608
X-RAY DIFFRACTIONr_angle_other_deg0.4951.575744
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.865328
X-RAY DIFFRACTIONr_dihedral_angle_2_deg8.1155.33315
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.02210447
X-RAY DIFFRACTIONr_dihedral_angle_6_deg15.56810121
X-RAY DIFFRACTIONr_chiral_restr0.0730.2381
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.023157
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02643
X-RAY DIFFRACTIONr_nbd_refined0.2210.2587
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1890.22372
X-RAY DIFFRACTIONr_nbtor_refined0.1860.21307
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0780.21373
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.2070.2252
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.2650.212
X-RAY DIFFRACTIONr_nbd_other0.2080.261
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.1980.224
X-RAY DIFFRACTIONr_mcbond_it3.3643.3331291
X-RAY DIFFRACTIONr_mcbond_other3.3643.3331291
X-RAY DIFFRACTIONr_mcangle_it5.1635.9611626
X-RAY DIFFRACTIONr_mcangle_other5.1645.9641627
X-RAY DIFFRACTIONr_scbond_it4.0233.7661366
X-RAY DIFFRACTIONr_scbond_other4.0213.7641367
X-RAY DIFFRACTIONr_scangle_it6.5076.6781982
X-RAY DIFFRACTIONr_scangle_other6.5066.6781983
X-RAY DIFFRACTIONr_lrange_it9.31137.9743265
X-RAY DIFFRACTIONr_lrange_other9.18835.1493154
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.925-1.9750.261870.2441850X-RAY DIFFRACTION98.1256
1.975-2.0290.2671060.2061766X-RAY DIFFRACTION97.9592
2.029-2.0880.24820.1911725X-RAY DIFFRACTION97.6757
2.088-2.1520.236760.1841660X-RAY DIFFRACTION97.8579
2.152-2.2220.2221000.1621613X-RAY DIFFRACTION97.8857
2.222-2.2990.202700.1561598X-RAY DIFFRACTION97.8873
2.299-2.3860.217820.1431526X-RAY DIFFRACTION97.6914
2.386-2.4830.217870.1451442X-RAY DIFFRACTION98.0757
2.483-2.5920.185550.1421399X-RAY DIFFRACTION97.1925
2.592-2.7180.209600.1461335X-RAY DIFFRACTION97.4843
2.718-2.8640.207620.1491277X-RAY DIFFRACTION97.4527
2.864-3.0360.226720.1461230X-RAY DIFFRACTION98.4871
3.036-3.2440.214580.1541119X-RAY DIFFRACTION97.5145
3.244-3.50.199520.1491070X-RAY DIFFRACTION98.5075
3.5-3.830.181480.141956X-RAY DIFFRACTION97.4757
3.83-4.2740.161360.129894X-RAY DIFFRACTION97.2803
4.274-4.9210.229370.123756X-RAY DIFFRACTION96.7073
4.921-5.9910.184280.167670X-RAY DIFFRACTION96.2759
5.991-8.3270.163190.151505X-RAY DIFFRACTION94.0754
8.327-31.8950.194140.143287X-RAY DIFFRACTION93.4783

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