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- PDB-3dpk: cFMS tyrosine kinase in complex with a pyridopyrimidinone inhibitor -

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Basic information

Entry
Database: PDB / ID: 3dpk
TitlecFMS tyrosine kinase in complex with a pyridopyrimidinone inhibitor
ComponentsMacrophage colony-stimulating factor 1 receptor, Fibroblast growth factor receptor 1
KeywordsTRANSFERASE / RECEPTOR TYROSINE KINASE / KINASE-INHIBITOR COMPLEX / ATP-binding / Glycoprotein / Immunoglobulin domain / Kinase / Membrane / Nucleotide-binding / Phosphoprotein / Proto-oncogene / Receptor / Transmembrane / Tyrosine-protein kinase / Craniosynostosis / Disease mutation / Dwarfism / Heparin-binding / Kallmann syndrome
Function / homology
Function and homology information


macrophage colony-stimulating factor receptor activity / CSF1-CSF1R complex / forebrain neuron differentiation / macrophage colony-stimulating factor signaling pathway / regulation of macrophage migration / Signaling by FGFR1 amplification mutants / diphosphate metabolic process / cellular response to macrophage colony-stimulating factor stimulus / positive regulation of protein tyrosine kinase activity / FGFR1c and Klotho ligand binding and activation ...macrophage colony-stimulating factor receptor activity / CSF1-CSF1R complex / forebrain neuron differentiation / macrophage colony-stimulating factor signaling pathway / regulation of macrophage migration / Signaling by FGFR1 amplification mutants / diphosphate metabolic process / cellular response to macrophage colony-stimulating factor stimulus / positive regulation of protein tyrosine kinase activity / FGFR1c and Klotho ligand binding and activation / Signaling by plasma membrane FGFR1 fusions / cell-cell junction maintenance / cementum mineralization / chordate embryonic development / response to sodium phosphate / Epithelial-Mesenchymal Transition (EMT) during gastrulation / fibroblast growth factor receptor signaling pathway involved in orbitofrontal cortex development / ventricular zone neuroblast division / microglial cell proliferation / positive regulation of phospholipase activity / receptor-receptor interaction / mammary gland duct morphogenesis / olfactory bulb development / regulation of postsynaptic density assembly / FGFR1b ligand binding and activation / Signaling by activated point mutants of FGFR1 / FGFR1c ligand binding and activation / Downstream signaling of activated FGFR1 / fibroblast growth factor receptor activity / Phospholipase C-mediated cascade: FGFR1 / host-mediated activation of viral process / ruffle organization / positive regulation of macrophage proliferation / skeletal system morphogenesis / regulation of bone resorption / positive regulation of vascular endothelial cell proliferation / positive regulation of endothelial cell chemotaxis / Other interleukin signaling / positive regulation of cell motility / positive regulation of tyrosine phosphorylation of STAT protein / Formation of paraxial mesoderm / growth factor binding / PI-3K cascade:FGFR1 / positive regulation of macrophage chemotaxis / cellular response to cytokine stimulus / positive regulation of MAP kinase activity / cytokine binding / fibroblast growth factor receptor signaling pathway / phosphatidylinositol-mediated signaling / macrophage differentiation / regulation of cell differentiation / Transcriptional Regulation by VENTX / fibroblast growth factor binding / monocyte differentiation / regulation of MAPK cascade / hemopoiesis / epithelial to mesenchymal transition / PI3K Cascade / positive regulation of blood vessel endothelial cell migration / calcium ion homeostasis / SHC-mediated cascade:FGFR1 / positive regulation of chemokine production / FRS-mediated FGFR1 signaling / cellular response to fibroblast growth factor stimulus / peptidyl-tyrosine phosphorylation / osteoclast differentiation / positive regulation of neuron differentiation / Signaling by FGFR1 in disease / positive regulation of cell cycle / NCAM signaling for neurite out-growth / SH2 domain binding / cell surface receptor protein tyrosine kinase signaling pathway / response to ischemia / axon guidance / Signal transduction by L1 / regulation of actin cytoskeleton organization / skeletal system development / positive regulation of cell differentiation / Negative regulation of FGFR1 signaling / receptor protein-tyrosine kinase / positive regulation of protein phosphorylation / neuron migration / Constitutive Signaling by Aberrant PI3K in Cancer / cytokine-mediated signaling pathway / Signaling by CSF1 (M-CSF) in myeloid cells / MAPK cascade / PIP3 activates AKT signaling / protein autophosphorylation / regulation of cell shape / cell migration / heparin binding / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / RAF/MAP kinase cascade / protein tyrosine kinase activity / cytoplasmic vesicle / protein phosphatase binding / protein phosphorylation / positive regulation of MAPK cascade / positive regulation of ERK1 and ERK2 cascade / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction
Similarity search - Function
Macrophage colony-stimulating factor 1 receptor / Platelet-derived growth factor receptor Ig-like domain 4 / Fibroblast growth factor receptor 1, catalytic domain / Tyrosine-protein kinase, receptor class III, conserved site / Receptor tyrosine kinase class III signature. / Fibroblast growth factor receptor family / Immunoglobulin / Immunoglobulin domain / Immunoglobulin I-set / Immunoglobulin I-set domain ...Macrophage colony-stimulating factor 1 receptor / Platelet-derived growth factor receptor Ig-like domain 4 / Fibroblast growth factor receptor 1, catalytic domain / Tyrosine-protein kinase, receptor class III, conserved site / Receptor tyrosine kinase class III signature. / Fibroblast growth factor receptor family / Immunoglobulin / Immunoglobulin domain / Immunoglobulin I-set / Immunoglobulin I-set 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 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / 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 / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-8C5 / Macrophage colony-stimulating factor 1 receptor / Fibroblast growth factor receptor 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.95 Å
AuthorsSchubert, C.
CitationJournal: J.Med.Chem. / Year: 2009
Title: Pyrido[2,3-d]pyrimidin-5-ones: a novel class of antiinflammatory macrophage colony-stimulating factor-1 receptor inhibitors
Authors: Huang, H. / Hutta, D.A. / Rinker, J.M. / Hu, H. / Parsons, W.H. / Schubert, C. / DesJarlais, R.L. / Crysler, C.S. / Chaikin, M.A. / Donatelli, R.R. / Chen, Y. / Cheng, D. / Zhou, Z. / ...Authors: Huang, H. / Hutta, D.A. / Rinker, J.M. / Hu, H. / Parsons, W.H. / Schubert, C. / DesJarlais, R.L. / Crysler, C.S. / Chaikin, M.A. / Donatelli, R.R. / Chen, Y. / Cheng, D. / Zhou, Z. / Yurkow, E. / Manthey, C.L. / Player, M.R.
History
DepositionJul 8, 2008Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 17, 2009Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Jan 25, 2017Group: Database references / Source and taxonomy
Revision 1.3Jul 26, 2017Group: Source and taxonomy / Category: entity_src_gen
Revision 1.4Oct 25, 2017Group: Refinement description / Category: software
Revision 1.5Aug 30, 2023Group: 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_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)38,8435
Polymers38,0641
Non-polymers7794
Water2,216123
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)80.950, 80.950, 145.420
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number146
Space group name H-MH3

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Components

#1: Protein Macrophage colony-stimulating factor 1 receptor, Fibroblast growth factor receptor 1 / CSF-1 receptor / CSF-1-R / CSF-1R / M-CSF-R / Proto-oncogene c-Fms / FGFR-1 / Basic fibroblast ...CSF-1 receptor / CSF-1-R / CSF-1R / M-CSF-R / Proto-oncogene c-Fms / FGFR-1 / Basic fibroblast growth factor receptor 1 / BFGFR / bFGF-R-1 / Fms-like tyrosine kinase 2 / FLT-2 / N-sam / Proto-oncogene c-Fgr


Mass: 38064.477 Da / Num. of mol.: 1 / Fragment: KINASE DOMAIN
Mutation: Native kinase insert domain replaced by FGF receptor kinase insert domain
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human)
Gene: CSF1R, FGFBR, FGFR1, FLG, FLT2, FMS, BFGFR, CEK, HBGFR
Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P07333, UniProt: P11362, receptor protein-tyrosine kinase
#2: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-8C5 / 8-cyclohexyl-N-methoxy-5-oxo-2-{[4-(2-pyrrolidin-1-ylethyl)phenyl]amino}-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide


Mass: 490.597 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H34N6O3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 123 / Source method: isolated from a natural source / Formula: H2O

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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: 2.41 Å3/Da / Density % sol: 48.94 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 5.2
Details: PEG 3350, SODIUM ACETATE, LI2SO4, pH 5.2, VAPOR DIFFUSION, HANGING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Nov 19, 2005
RadiationMonochromator: SAGITALLY FOCUSED Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.8→50 Å / Num. all: 27585 / Num. obs: 27585 / % possible obs: 83.8 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -3 / Redundancy: 3.6 % / Rmerge(I) obs: 0.093 / Net I/σ(I): 12.2
Reflection shellResolution: 1.8→1.86 Å / Redundancy: 3.6 % / Rmerge(I) obs: 0.276 / Mean I/σ(I) obs: 4.3 / Num. unique all: 3289 / % possible all: 99.6

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Processing

Software
NameVersionClassification
PHENIX(phenix.refine)refinement
HKL-2000data reduction
HKL-2000data scaling
CNXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2i1m

2i1m


Resolution: 1.95→34.1 Å / Isotropic thermal model: isotropic / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
Details: Isotropic B-factor refinement for non-hydrogen atoms. Hydrogens were assigned the B-factor of their "parent" atom and one B-factor for all hydrogens was refined, as implemented in phenix
RfactorNum. reflection% reflectionSelection details
Rfree0.2441 2172 9.85 %Random
Rwork0.1862 ---
all0.192 22043 --
obs0.192 22043 85 %-
Displacement parametersBiso mean: 28.61 Å2
Refinement stepCycle: LAST / Resolution: 1.95→34.1 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2208 0 51 123 2382
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONf_bond_d0.01
X-RAY DIFFRACTIONf_angle_deg1.018
X-RAY DIFFRACTIONf_improper_angle_d0.076
X-RAY DIFFRACTIONf_dihedral_angle_d17.4
X-RAY DIFFRACTIONf_planarity_d0.009

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