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- PDB-3krj: cFMS tyrosine kinase in complex with 4-Cyano-1H-imidazole-2-carbo... -

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Basic information

Entry
Database: PDB / ID: 3krj
TitlecFMS tyrosine kinase in complex with 4-Cyano-1H-imidazole-2-carboxylic acid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide
ComponentsMacrophage colony-stimulating factor 1 receptor, Basic fibroblast growth factor receptor 1
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Kinase / inhibitor / chimera / ATP-binding / Disulfide bond / Glycoprotein / Immunoglobulin domain / Membrane / Nucleotide-binding / Phosphoprotein / Proto-oncogene / Receptor / Transferase / Transmembrane / Tyrosine-protein kinase / TRANSFERASE-TRANSFERASE INHIBITOR complex
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 / microglial cell proliferation / Signaling by FGFR1 amplification mutants / cellular response to macrophage colony-stimulating factor stimulus / diphosphate metabolic process / 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 / microglial cell proliferation / Signaling by FGFR1 amplification mutants / cellular response to macrophage colony-stimulating factor stimulus / diphosphate metabolic process / FGFR1c and Klotho ligand binding and activation / Signaling by plasma membrane FGFR1 fusions / cell-cell junction maintenance / mammary gland duct morphogenesis / positive regulation of protein tyrosine kinase activity / 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 / receptor-receptor interaction / positive regulation of phospholipase activity / olfactory bulb development / FGFR1b ligand binding and activation / positive regulation of cell motility / regulation of postsynaptic density assembly / Signaling by activated point mutants of FGFR1 / FGFR1c ligand binding and activation / Downstream signaling of activated FGFR1 / Phospholipase C-mediated cascade: FGFR1 / fibroblast growth factor receptor activity / host-mediated activation of viral process / ruffle organization / skeletal system morphogenesis / positive regulation of macrophage proliferation / regulation of bone resorption / positive regulation of vascular endothelial cell proliferation / positive regulation of endothelial cell chemotaxis / Other interleukin signaling / fibroblast growth factor receptor signaling pathway / Formation of paraxial mesoderm / growth factor binding / positive regulation of tyrosine phosphorylation of STAT protein / PI-3K cascade:FGFR1 / hemopoiesis / positive regulation of macrophage chemotaxis / positive regulation of MAP kinase activity / cellular response to cytokine stimulus / cytokine binding / macrophage differentiation / regulation of cell differentiation / phosphatidylinositol-mediated signaling / monocyte differentiation / Transcriptional Regulation by VENTX / fibroblast growth factor binding / epithelial to mesenchymal transition / regulation of MAPK cascade / PI3K Cascade / skeletal system development / positive regulation of blood vessel endothelial cell migration / response to ischemia / osteoclast differentiation / positive regulation of neuron differentiation / calcium ion homeostasis / positive regulation of chemokine production / SHC-mediated cascade:FGFR1 / FRS-mediated FGFR1 signaling / cellular response to fibroblast growth factor stimulus / positive regulation of cell cycle / peptidyl-tyrosine phosphorylation / Signaling by FGFR1 in disease / NCAM signaling for neurite out-growth / axon guidance / SH2 domain binding / cell surface receptor protein tyrosine kinase signaling pathway / Signal transduction by L1 / regulation of actin cytoskeleton organization / positive regulation of cell differentiation / neuron migration / Negative regulation of FGFR1 signaling / receptor protein-tyrosine kinase / positive regulation of protein phosphorylation / cell population proliferation / cytokine-mediated signaling pathway / Constitutive Signaling by Aberrant PI3K in Cancer / regulation of cell shape / Signaling by CSF1 (M-CSF) in myeloid cells / MAPK cascade / PIP3 activates AKT signaling / protein autophosphorylation / 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 / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of MAPK cascade / positive regulation of ERK1 and ERK2 cascade
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
ACETATE ION / Chem-KRJ / 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: 2.1 Å
AuthorsSchubert, C.
CitationJournal: J.Med.Chem. / Year: 2011
Title: Optimization of a Potent Class of Arylamide Colony-Stimulating Factor-1 Receptor Inhibitors Leading to Anti-inflammatory Clinical Candidate 4-Cyano-N-[2-(1-cyclohexen-1-yl)-4-[1- ...Title: Optimization of a Potent Class of Arylamide Colony-Stimulating Factor-1 Receptor Inhibitors Leading to Anti-inflammatory Clinical Candidate 4-Cyano-N-[2-(1-cyclohexen-1-yl)-4-[1-[(dimethylamino)acetyl]-4-piperidinyl]phenyl]-1H-imidazole-2-carboxamide (JNJ-28312141).
Authors: Illig, C.R. / Manthey, C.L. / Wall, M.J. / Meegalla, S.K. / Chen, J. / Wilson, K.J. / Ballentine, S.K. / Desjarlais, R.L. / Schubert, C. / Crysler, C.S. / Chen, Y. / Molloy, C.J. / Chaikin, ...Authors: Illig, C.R. / Manthey, C.L. / Wall, M.J. / Meegalla, S.K. / Chen, J. / Wilson, K.J. / Ballentine, S.K. / Desjarlais, R.L. / Schubert, C. / Crysler, C.S. / Chen, Y. / Molloy, C.J. / Chaikin, M.A. / Donatelli, R.R. / Yurkow, E. / Zhou, Z. / Player, M.R. / Tomczuk, B.E.
History
DepositionNov 18, 2009Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 1, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Dec 14, 2011Group: Database references
Revision 1.3Aug 23, 2017Group: Source and taxonomy / Category: entity_src_gen
Revision 1.4Oct 13, 2021Group: Database references / Derived calculations / Category: database_2 / 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
Revision 1.5Sep 6, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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, Basic fibroblast growth factor receptor 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,4993
Polymers38,0641
Non-polymers4352
Water2,558142
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)82.875, 82.875, 144.408
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, Basic fibroblast growth factor receptor 1 / c-fms / FGFR-1


Mass: 38064.477 Da / Num. of mol.: 1 / Fragment: UNP residues 538-678, 753-922 / Mutation: C584S
Source method: isolated from a genetically manipulated source
Details: Native kinase insert domain of c-fms replaced by FGF receptor kinase insert domain
Source: (gene. exp.) Homo sapiens (human) / Gene: CSF1R, FMS, FGFR1 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P07333, UniProt: P11362, receptor protein-tyrosine kinase
#2: Chemical ChemComp-ACT / ACETATE ION


Mass: 59.044 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H3O2
#3: Chemical ChemComp-KRJ / 4-cyano-N-(2-cyclohex-1-en-1-yl-4-piperidin-4-ylphenyl)-1H-imidazole-2-carboxamide


Mass: 375.467 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H25N5O
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 142 / 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: 2.51 Å3/Da / Density % sol: 50.94 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 5.6
Details: 13-19%PRG3350 100mM NaAcetate, pH 5.6 200mM (NH4)2SO4, VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: MAR CCD 165 mm / Detector: CCD / Date: May 1, 2004
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.1→16.4 Å / Num. obs: 21192 / % possible obs: 97.2 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -3 / Redundancy: 3.5 % / Rmerge(I) obs: 0.075 / Net I/σ(I): 15.3
Reflection shellResolution: 2.1→2.17 Å / Redundancy: 3.8 % / Rmerge(I) obs: 0.29 / Mean I/σ(I) obs: 4.1 / Num. unique all: 2181 / % possible all: 100

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Processing

Software
NameClassification
PHENIXmodel building
PHENIXrefinement
HKL-2000data reduction
HKL-2000data scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 2i0v

2i0v


Resolution: 2.1→16.4 Å / SU ML: 0.36 / Isotropic thermal model: isotropic, TLS / Cross valid method: THROUGHOUT / σ(F): 0.07 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2602 1924 9.43 %random
Rwork0.2079 ---
obs0.2128 20404 93.31 %-
all-20404 --
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 63.127 Å2 / ksol: 0.465 e/Å3
Refinement stepCycle: LAST / Resolution: 2.1→16.4 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2399 0 32 142 2573
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0032499
X-RAY DIFFRACTIONf_angle_d0.8883384
X-RAY DIFFRACTIONf_dihedral_angle_d18.678901
X-RAY DIFFRACTIONf_chiral_restr0.053363
X-RAY DIFFRACTIONf_plane_restr0.006431
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.1-2.14280.29131380.22131289X-RAY DIFFRACTION91
2.1428-2.20060.26691410.22281352X-RAY DIFFRACTION97
2.2006-2.26520.35151200.26621231X-RAY DIFFRACTION86
2.2652-2.33810.26991220.23271226X-RAY DIFFRACTION85
2.3381-2.42140.28521420.20881341X-RAY DIFFRACTION96
2.4214-2.51810.24731420.19421372X-RAY DIFFRACTION97
2.5181-2.63220.29261460.18971345X-RAY DIFFRACTION97
2.6322-2.77040.23871430.19141402X-RAY DIFFRACTION98
2.7704-2.9430.26751520.1881402X-RAY DIFFRACTION99
2.943-3.16870.24131410.18481386X-RAY DIFFRACTION99
3.1687-3.48490.23821480.17021410X-RAY DIFFRACTION99
3.4849-3.98290.22581470.1681383X-RAY DIFFRACTION96
3.9829-4.99440.22121180.18121190X-RAY DIFFRACTION85
4.9944-16.40.24851240.22541151X-RAY DIFFRACTION81
Refinement TLS params.

Refine-ID: X-RAY DIFFRACTION

IDMethodL11 (°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)
1refined0.9889-0.2948-0.19780.2803-0.18410.3387-0.1795-0.3565-0.08110.0580.25080.3720.13750.1745-0.09920.15520.06760.00380.2924-0.08070.476727.699441.0395-7.1103
21.3919-0.1216-0.08630.51410.82711.4002-0.4823-0.1127-0.99951.07960.4820.65150.9956-0.10110.04740.55610.20170.22210.35660.21930.4592
31.966-0.8803-0.77623.9494-0.90671.4743-0.404-0.1045-0.60181.01120.48821.24760.2561-0.25560.02370.3810.15880.24280.22830.13840.373
43.06740.19480.2870.33850.40530.4978-0.50790.33310.46860.28550.12730.14330.17980.13870.29390.26920.00420.0540.2644-0.0150.3875
52.2711-0.6097-1.03222.9304-4.36878.26420.4373-0.233-0.32070.2377-0.4350.9952-0.52790.8114-0.07950.24160.1061-0.03410.2160.0070.226
61.3167-0.5261-0.58830.8050.20941.1396-0.1341-0.101-0.17620.26260.07660.5630.01150.01570.04440.36430.14180.11290.22330.04920.2726
71.4194-0.41041.45660.31390.11273.6228-0.47250.1444-0.51180.51580.23671.03310.02990.38240.35440.57060.20180.24480.18930.10840.6314
80.36940.53210.03592.0153-0.76822.1947-0.04460.04280.12280.37880.1897-0.1263-0.232-0.1176-0.1090.25060.0483-0.00120.1523-0.00860.1875
90.6913-0.0071-0.23271.23020.29821.1639-0.07620.2881-0.0837-0.19170.07920.11420.0194-0.2029-0.00060.26630.005-0.02850.21160.01520.1766
102.14180.2377-0.85011.41230.02540.7973-0.0480.18430.21470.0131-0.0065-0.5223-0.31320.14140.02390.2437-0.0027-0.01220.10610.01160.2894
Refinement TLS groupSelection details: chain A and resid 869:912)

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