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- PDB-7tnh: Crystal structure of CSF1R kinase domain in complex with DP-6233 -

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Basic information

Entry
Database: PDB / ID: 7tnh
TitleCrystal structure of CSF1R kinase domain in complex with DP-6233
ComponentsMacrophage colony-stimulating factor 1 receptor,Fibroblast growth factor receptor 1 chimera
KeywordsTRANSFERASE / human CSR1R kinase / cancer
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 / 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 ...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 / 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 / Signaling by plasma membrane FGFR1 fusions / diphosphate metabolic process / FGFR1c and Klotho ligand binding and activation / vitamin D3 metabolic process / regulation of phosphate transport / cellular response to macrophage colony-stimulating factor stimulus / regulation of lateral mesodermal cell fate specification / positive regulation of MAPKKK cascade by fibroblast growth factor receptor signaling pathway / cementum mineralization / response to sodium phosphate / regulation of branching involved in salivary gland morphogenesis by mesenchymal-epithelial signaling / receptor-receptor interaction / fibroblast growth factor receptor signaling pathway involved in orbitofrontal cortex development / auditory receptor cell development / microglial cell proliferation / ventricular zone neuroblast division / Epithelial-Mesenchymal Transition (EMT) during gastrulation / positive regulation of parathyroid hormone secretion / chordate embryonic development / mesenchymal cell proliferation / paraxial mesoderm development / olfactory bulb development / FGFR1b ligand binding and activation / fibroblast growth factor receptor activity / branching involved in salivary gland morphogenesis / mammary gland duct morphogenesis / Signaling by activated point mutants of FGFR1 / FGFR1c ligand binding and activation / organ induction / Downstream signaling of activated FGFR1 / Phospholipase C-mediated cascade: FGFR1 / positive regulation of phospholipase activity / positive regulation by host of viral process / ruffle organization / lung-associated mesenchyme development / cell projection assembly / cellular response to fibroblast growth factor stimulus / positive regulation of macrophage proliferation / outer ear morphogenesis / middle ear morphogenesis / positive regulation of cell motility / regulation of bone resorption / embryonic limb morphogenesis / skeletal system morphogenesis / positive regulation of endothelial cell chemotaxis / positive regulation of mesenchymal cell proliferation / cardiac muscle cell proliferation / positive regulation of vascular endothelial cell proliferation / ureteric bud development / inner ear morphogenesis / midbrain development / Other interleukin signaling / positive regulation of macrophage chemotaxis / fibroblast growth factor binding / cytokine binding / positive regulation of stem cell proliferation / Formation of paraxial mesoderm / PI-3K cascade:FGFR1 / regulation of cell differentiation / growth factor binding / cellular response to cytokine stimulus / phosphatidylinositol-mediated signaling / regulation of MAPK cascade / monocyte differentiation / hemopoiesis / macrophage differentiation / Transcriptional Regulation by VENTX / positive regulation of protein tyrosine kinase activity / PI3K Cascade / epithelial to mesenchymal transition / positive regulation of blood vessel endothelial cell migration / fibroblast growth factor receptor signaling pathway / calcium ion homeostasis / chondrocyte differentiation / : / SHC-mediated cascade:FGFR1 / positive regulation of chemokine production / cell maturation / positive regulation of tyrosine phosphorylation of STAT protein / positive regulation of cardiac muscle cell proliferation / FRS-mediated FGFR1 signaling / positive regulation of neuron differentiation / Signaling by FGFR1 in disease / NCAM signaling for neurite out-growth / SH2 domain binding / osteoclast differentiation / Signal transduction by L1 / skeletal system development / stem cell proliferation / response to ischemia
Similarity search - Function
Macrophage colony-stimulating factor 1 receptor / 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 domain / Immunoglobulin I-set / Immunoglobulin I-set domain ...Macrophage colony-stimulating factor 1 receptor / 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 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 / 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
Chem-I9W / 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: 2.7 Å
AuthorsEdwards, T.E. / Arakaki, T.L. / Chun, L. / Flynn, D.L.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2022
Title: Discovery of acyl ureas as highly selective small molecule CSF1R kinase inhibitors.
Authors: Caldwell, T.M. / Kaufman, M.D. / Wise, S.C. / Mi Ahn, Y. / Hood, M.M. / Lu, W.P. / Patt, W.C. / Samarakoon, T. / Vogeti, L. / Vogeti, S. / Yates, K.M. / Bulfer, S.L. / Le Bourdonnec, B. / ...Authors: Caldwell, T.M. / Kaufman, M.D. / Wise, S.C. / Mi Ahn, Y. / Hood, M.M. / Lu, W.P. / Patt, W.C. / Samarakoon, T. / Vogeti, L. / Vogeti, S. / Yates, K.M. / Bulfer, S.L. / Le Bourdonnec, B. / Smith, B.D. / Flynn, D.L.
History
DepositionJan 21, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 24, 2022Provider: repository / Type: Initial release
Revision 1.1Aug 31, 2022Group: Database references / Category: citation / Item: _citation.journal_volume / _citation.title
Revision 1.2Oct 18, 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,Fibroblast growth factor receptor 1 chimera
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,0837
Polymers38,5101
Non-polymers5736
Water1629
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)81.080, 81.080, 146.670
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-1002-

CL

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Components

#1: Protein Macrophage colony-stimulating factor 1 receptor,Fibroblast growth factor receptor 1 chimera / 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: 38509.812 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: CSF1R residues 549-922 with the native KID substituted with the KID of FGFR
Source: (gene. exp.) Homo sapiens (human)
Gene: CSF1R, FMS, FGFR1, BFGFR, CEK, FGFBR, FLG, FLT2, HBGFR
Plasmid: VCID 7143 / Production host: Trichoplusia ni (cabbage looper)
References: UniProt: P07333, UniProt: P11362, receptor protein-tyrosine kinase
#2: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#3: Chemical
ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Cl
#4: Chemical ChemComp-I9W / 2,2-dimethyl-N-[(6-methyl-5-{[2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl]oxy}pyridin-2-yl)carbamoyl]propanamide


Mass: 408.454 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H24N6O3 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 9 / 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: 2.4 Å3/Da / Density % sol: 49 %
Crystal growTemperature: 295 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: CSF1R at 10.7 mg/mL in 50 mM Tris pH 7.5, 200 mM NaCl, 5% glycerol with 5-fold excess of arylamide compound against 10% PEG 10,000, 0.1 M MES pH 6.5 and 0.1 M magnesium acetate soaked over ...Details: CSF1R at 10.7 mg/mL in 50 mM Tris pH 7.5, 200 mM NaCl, 5% glycerol with 5-fold excess of arylamide compound against 10% PEG 10,000, 0.1 M MES pH 6.5 and 0.1 M magnesium acetate soaked over two nights with 1 mM DP-6233 and 20% ethylene glycol as cryo

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-F / Wavelength: 0.97857 Å
DetectorType: RAYONIX MX-225 / Detector: CCD / Date: Aug 10, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97857 Å / Relative weight: 1
ReflectionResolution: 2.7→40.57 Å / Num. obs: 9752 / % possible obs: 98.8 % / Redundancy: 3.2 % / Biso Wilson estimate: 70.8 Å2 / Rmerge F obs: 0.115 / Rmerge(I) obs: 0.044 / Rrim(I) all: 0.053 / Χ2: 0.974 / Net I/σ(I): 19.95 / Num. measured all: 31405
Reflection shellResolution: 2.7→40.57 Å / Redundancy: 3.2 % / Rmerge F obs: 0.014 / Rmerge(I) obs: 0.577 / Mean I/σ(I) obs: 2 / Num. measured obs: 305 / Num. possible: 114 / Num. unique obs: 99 / Rrim(I) all: 0.018 / % possible all: 99.3

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Processing

Software
NameVersionClassification
XSCALEdata scaling
REFMAC5.7.0029refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2I0Y

2i0y


Resolution: 2.7→40.57 Å / Cor.coef. Fo:Fc: 0.944 / Cor.coef. Fo:Fc free: 0.924 / SU B: 33.582 / SU ML: 0.316 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.97 / ESU R Free: 0.355 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: U VALUES : WITH TLS ADDED HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.269 471 4.8 %RANDOM
Rwork0.215 ---
obs0.217 9749 98.8 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 165.87 Å2 / Biso mean: 71.98 Å2 / Biso min: 30.82 Å2
Baniso -1Baniso -2Baniso -3
1--2.89 Å2-2.89 Å2-0 Å2
2---2.89 Å20 Å2
3---9.39 Å2
Refinement stepCycle: final / Resolution: 2.7→40.57 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2078 0 35 9 2122
Biso mean--73.83 53.59 -
Num. residues----280
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0192158
X-RAY DIFFRACTIONr_bond_other_d0.0010.021954
X-RAY DIFFRACTIONr_angle_refined_deg1.2341.9572939
X-RAY DIFFRACTIONr_angle_other_deg0.74834437
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.985274
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.6123.6984
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.05715299
X-RAY DIFFRACTIONr_dihedral_angle_4_deg24.143158
X-RAY DIFFRACTIONr_chiral_restr0.0590.2328
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0212481
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02516
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.7→2.77 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.286 33 -
Rwork0.295 674 -
all-707 -
obs--99.3 %
Refinement TLS params.Method: refined / Origin x: 14.614 Å / Origin y: 28.356 Å / Origin z: -0.932 Å
111213212223313233
T0.1638 Å2-0.0078 Å2-0.0441 Å2-0.1714 Å20.0058 Å2--0.0247 Å2
L0.8525 °21.2751 °2-0.4921 °2-3.5195 °2-0.6809 °2--0.6488 °2
S0.2064 Å °-0.0548 Å °-0.1359 Å °0.0683 Å °-0.2615 Å °-0.163 Å °-0.0632 Å °0.1072 Å °0.0551 Å °

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