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- PDB-3krl: cFMS Tyrosine kinase in complex with 5-Cyano-furan-2-carboxylic a... -

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Basic information

Entry
Database: PDB / ID: 3krl
TitlecFMS Tyrosine kinase in complex with 5-Cyano-furan-2-carboxylic acid [4-(4-methyl-piperazin-1-yl)-2-piperidin-1-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


forebrain neuron differentiation / macrophage colony-stimulating factor receptor activity / CSF1-CSF1R complex / macrophage colony-stimulating factor signaling pathway / regulation of macrophage migration / Signaling by FGFR1 amplification mutants / negative regulation of fibroblast growth factor production / positive regulation of mitotic cell cycle DNA replication / regulation of extrinsic apoptotic signaling pathway in absence of ligand / diphosphate metabolic process ...forebrain neuron differentiation / macrophage colony-stimulating factor receptor activity / CSF1-CSF1R complex / macrophage colony-stimulating factor signaling pathway / regulation of macrophage migration / Signaling by FGFR1 amplification mutants / negative regulation of fibroblast growth factor production / positive regulation of mitotic cell cycle DNA replication / regulation of extrinsic apoptotic signaling pathway in absence of ligand / diphosphate metabolic process / Signaling by plasma membrane FGFR1 fusions / cellular response to macrophage colony-stimulating factor stimulus / regulation of phosphate transport / FGFR1c and Klotho ligand binding and activation / cell-cell junction maintenance / regulation of lateral mesodermal cell fate specification / positive regulation of MAPKKK cascade by fibroblast growth factor receptor signaling pathway / vitamin D3 metabolic process / cementum mineralization / regulation of branching involved in salivary gland morphogenesis by mesenchymal-epithelial signaling / response to sodium phosphate / fibroblast growth factor receptor signaling pathway involved in orbitofrontal cortex development / ventricular zone neuroblast division / Epithelial-Mesenchymal Transition (EMT) during gastrulation / positive regulation of phospholipase activity / microglial cell proliferation / receptor-receptor interaction / chordate embryonic development / positive regulation of parathyroid hormone secretion / auditory receptor cell development / mesenchymal cell proliferation / paraxial mesoderm development / olfactory bulb development / mammary gland duct morphogenesis / FGFR1b ligand binding and activation / regulation of postsynaptic density assembly / Signaling by activated point mutants of FGFR1 / fibroblast growth factor receptor activity / FGFR1c ligand binding and activation / organ induction / Downstream signaling of activated FGFR1 / branching involved in salivary gland morphogenesis / Phospholipase C-mediated cascade: FGFR1 / lung-associated mesenchyme development / host-mediated activation of viral process / cell projection assembly / ruffle organization / positive regulation of macrophage proliferation / outer ear morphogenesis / embryonic limb morphogenesis / regulation of bone resorption / positive regulation of endothelial cell chemotaxis / positive regulation of vascular endothelial cell proliferation / positive regulation of mesenchymal cell proliferation / ureteric bud development / middle ear morphogenesis / skeletal system morphogenesis / positive regulation of cell motility / Other interleukin signaling / positive regulation of tyrosine phosphorylation of STAT protein / inner ear morphogenesis / growth factor binding / positive regulation of protein tyrosine kinase activity / phosphatidylinositol-mediated signaling / PI-3K cascade:FGFR1 / positive regulation of stem cell proliferation / Formation of paraxial mesoderm / positive regulation of macrophage chemotaxis / midbrain development / cytokine binding / cellular response to cytokine stimulus / fibroblast growth factor binding / positive regulation of MAP kinase activity / regulation of cell differentiation / regulation of MAPK cascade / hemopoiesis / Transcriptional Regulation by VENTX / macrophage differentiation / monocyte differentiation / PI3K Cascade / epithelial to mesenchymal transition / fibroblast growth factor receptor signaling pathway / positive regulation of blood vessel endothelial cell migration / chondrocyte differentiation / cardiac muscle cell proliferation / calcium ion homeostasis / SHC-mediated cascade:FGFR1 / positive regulation of cardiac muscle cell proliferation / cell maturation / positive regulation of chemokine production / FRS-mediated FGFR1 signaling / cellular response to fibroblast growth factor stimulus / positive regulation of neuron differentiation / Signaling by FGFR1 in disease / NCAM signaling for neurite out-growth / SH2 domain binding / axon guidance / cell surface receptor protein tyrosine kinase signaling pathway / osteoclast differentiation / peptidyl-tyrosine phosphorylation
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 / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / 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-KRL / 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: 2.4 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

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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)38,5543
Polymers38,0641
Non-polymers4902
Water66737
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)81.111, 81.111, 142.570
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number146
Space group name H-MH3
Components on special symmetry positions
IDModelComponents
11A-923-

SO4

21A-923-

SO4

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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, FGFR1 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P07333, UniProt: P11362, receptor protein-tyrosine kinase
#2: Chemical ChemComp-KRL / 5-cyano-N-[4-(4-methylpiperazin-1-yl)-2-piperidin-1-ylphenyl]furan-2-carboxamide


Mass: 393.482 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H27N5O2
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 37 / 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: 2.37 Å3/Da / Density % sol: 48.13 %
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop / pH: 5.6
Details: 13-19% PEG3350 100mM NaAc pH 5.6 200mM (NH4)2SO4, VAPOR DIFFUSION, HANGING DROP, temperature 295K

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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: 2.4→16.16 Å / Num. all: 13458 / Num. obs: 13458 / % possible obs: 98.8 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -3 / Redundancy: 3.3 % / Rmerge(I) obs: 0.059 / Net I/σ(I): 18.2
Reflection shellResolution: 2.4→2.49 Å / Redundancy: 3.5 % / Rmerge(I) obs: 0.237 / Mean I/σ(I) obs: 4.8 / Num. unique all: 1333 / % 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: 2.4→16.16 Å / SU ML: 0.38 / Isotropic thermal model: Isotropic, TLS / Cross valid method: THROUGHOUT / σ(F): 0.04 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.264 639 4.97 %random
Rwork0.2091 ---
obs0.2119 12852 94.53 %-
all-12852 --
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 61.443 Å2 / ksol: 0.449 e/Å3
Refinement stepCycle: LAST / Resolution: 2.4→16.16 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2221 0 34 37 2292
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0032326
X-RAY DIFFRACTIONf_angle_d0.8153130
X-RAY DIFFRACTIONf_dihedral_angle_d19.026854
X-RAY DIFFRACTIONf_chiral_restr0.046338
X-RAY DIFFRACTIONf_plane_restr0.006395
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.4-2.58840.27071170.22782337X-RAY DIFFRACTION90
2.5884-2.84760.3261260.24432324X-RAY DIFFRACTION90
2.8476-3.25670.31021390.22042530X-RAY DIFFRACTION98
3.2567-4.0920.24521330.18282531X-RAY DIFFRACTION98
4.092-16.160.22831240.19512491X-RAY DIFFRACTION96
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)
1refined0.03670.0069-0.00470.04490.01830.07530.8331-0.35492.2662-1.3028-1.15270.0069-0.7315-0.5192-0.00610.6590.06770.0230.67940.16020.9373-7.1652-26.29018.1137
20.4583-0.2988-0.2830.50970.50270.49230.04490.8346-0.33630.12790.4767-0.5502-0.07260.1175-0.00030.34830.06730.04870.5416-0.02130.6134
31.5059-0.6858-0.5930.7854-0.43681.27780.12540.58810.5907-0.4710.4793-0.5754-0.46910.2370.00040.310.02960.07440.4012-0.08810.4225
40.7738-0.13420.37390.7846-0.06750.1843-0.69920.34650.5430.40510.7491.19690.40230.3510.00260.46390.1852-0.00880.4091-0.0030.5368
50.0687-0.01150.02580.1458-0.06860.03920.75310.72470.4072-0.4692-0.1212-0.54380.65940.0342-0.00190.4847-0.06890.070.4456-0.2580.6833
60.4267-0.33850.19520.2853-0.0910.2092-0.26340.43670.3157-0.09750.1989-0.253-0.0677-0.01370.00040.2910.0280.0230.4532-0.0190.3539
70.2394-0.58420.13712.8094-2.543.59210.47181.61680.09760.1773-0.5369-1.2884-0.99430.4187-0.14780.38850.29160.0680.71220.1120.314
82.3758-0.5603-1.58330.13170.36451.109-0.08740.0847-0.81070.02290.0620.1923-0.0037-0.09340.0050.2760.01950.04520.295-0.03050.3412
91.9161-0.7813-0.94081.8246-0.83471.4539-0.0999-0.131-0.14650.2447-0.0980.0577-0.13680.1857-0.00030.24690.0371-0.03370.29160.0470.1617
102.08520.0812-1.35531.7005-0.00362.0311-0.6101-0.2132-1.06820.6133-0.21630.60410.3783-0.1871-0.0010.3787-0.02040.18230.3860.00760.6378
Refinement TLS groupSelection details: chain A and resid 869:912)

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