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- PDB-6ig8: Crystal structure of CSF-1R kinase domain with a small molecular ... -

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Basic information

Entry
Database: PDB / ID: 6ig8
TitleCrystal structure of CSF-1R kinase domain with a small molecular inhibitor, JTE-952
ComponentsMacrophage colony-stimulating factor 1 receptor
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / CSF-1-R / FMS PROTO-ONCOGENE / C-FMS / CD115 antigen / Kinase / ATP-binding / TRANSFERASE-TRANSFERASE INHIBITOR complex
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 / growth factor binding / cellular response to cytokine stimulus / cytokine binding / 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 / axon guidance / response to ischemia / regulation of actin cytoskeleton organization / 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 ERK1 and ERK2 cascade / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / 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 ...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 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; 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-A7O / Macrophage colony-stimulating factor 1 receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.8 Å
AuthorsDoi, S. / Adachi, T.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2019
Title: Discovery of a novel azetidine scaffold for colony stimulating factor-1 receptor (CSF-1R) Type II inhibitors by the use of docking models.
Authors: Ikegashira, K. / Ikenogami, T. / Yamasaki, T. / Hase, Y. / Yamaguchi, T. / Inagaki, K. / Doi, S. / Adachi, T. / Koga, Y. / Hashimoto, H.
History
DepositionSep 25, 2018Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Aug 7, 2019Provider: repository / Type: Initial release
Revision 1.1Nov 22, 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 / pdbx_struct_conn_angle / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr1_symmetry / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.ptnr3_symmetry / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_symmetry

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,9405
Polymers36,2811
Non-polymers6594
Water6,666370
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area360 Å2
ΔGint-8 kcal/mol
Surface area14420 Å2
Unit cell
Length a, b, c (Å)62.520, 62.520, 185.310
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number96
Space group name H-MP43212
Components on special symmetry positions
IDModelComponents
11A-1427-

HOH

21A-1470-

HOH

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Components

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


Mass: 36280.562 Da / Num. of mol.: 1 / Mutation: S688A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CSF1R, FMS / Cell line (production host): sf9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P07333, receptor protein-tyrosine kinase
#2: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#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-A7O / (3-{4-[(4-cyclopropylphenyl)methoxy]-3-methoxyphenyl}azetidin-1-yl)(4-{[(2S)-2,3-dihydroxypropoxy]methyl}pyridin-2-yl)methanone


Mass: 518.601 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C30H34N2O6 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 370 / 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: 2.5 Å3/Da / Density % sol: 50.71 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 8.5
Details: 11 mg/mL protein, 22.5-35% PEG 4000, 0.1M Tris-HCL pH 8.5, 0.2M MgCl2

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-F / Wavelength: 0.97872 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Jun 12, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97872 Å / Relative weight: 1
ReflectionResolution: 1.8→59.24 Å / Num. obs: 35007 / % possible obs: 99.8 % / Redundancy: 8.3 % / Rpim(I) all: 0.031 / Rrim(I) all: 0.09 / Rsym value: 0.079 / Net I/av σ(I): 8.6 / Net I/σ(I): 18.8
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique obsRpim(I) allRrim(I) allRsym value% possible all
1.8-1.858.40.5241.425550.20.5920.524100
1.85-1.98.50.4481.724780.1710.5080.448100
1.9-1.958.30.381224100.1470.4310.381100
1.95-2.018.40.292.623610.110.3260.29100
2.01-2.088.40.2443.122490.0940.2770.24499.8
2.08-2.158.40.1983.822310.0750.2230.198100
2.15-2.238.40.1654.621330.0630.1870.165100
2.23-2.328.20.1425.320530.0560.1620.14299.9
2.32-2.438.40.1176.519570.0450.1320.11799.9
2.43-2.558.40.0997.619030.0380.1120.099100
2.55-2.688.40.0898.418130.0340.10.08999.7
2.68-2.858.40.0759.717250.0290.0850.075100
2.85-3.048.40.06211.616040.0240.070.06299.7
3.04-3.298.30.05213.615200.020.0590.05299.8
3.29-3.68.10.04415.313880.0180.050.04499.7
3.6-4.0280.03916.412790.0150.0440.03999.3
4.02-4.658.10.02922.311360.0110.0330.02999
4.65-5.6980.03219700.0120.0340.0398.7
5.69-8.057.60.03120.27710.0120.0350.03198.5
8.05-62.526.70.02423.44710.010.0270.02497.5

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Processing

Software
NameVersionClassification
REFMAC5.8.0232refinement
XDSdata reduction
SCALA3.3.16data scaling
PDB_EXTRACT3.24data extraction
REFMACphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3LCO

3lco


Resolution: 1.8→59.24 Å / Cor.coef. Fo:Fc: 0.965 / Cor.coef. Fo:Fc free: 0.945 / SU B: 2.225 / SU ML: 0.069 / SU R Cruickshank DPI: 0.1051 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.105 / ESU R Free: 0.104
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.1922 1751 5 %RANDOM
Rwork0.156 ---
obs0.1579 33140 99.38 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 98.44 Å2 / Biso mean: 20.164 Å2 / Biso min: 8.04 Å2
Baniso -1Baniso -2Baniso -3
1-0.48 Å2-0 Å2-0 Å2
2--0.48 Å2-0 Å2
3----0.95 Å2
Refinement stepCycle: final / Resolution: 1.8→59.24 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2368 0 46 373 2787
Biso mean--22.17 33.32 -
Num. residues----301
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0150.0132599
X-RAY DIFFRACTIONr_bond_other_d0.0010.0172424
X-RAY DIFFRACTIONr_angle_refined_deg1.7041.6523538
X-RAY DIFFRACTIONr_angle_other_deg1.5881.5915641
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.6075326
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.78522.984124
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.49815442
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.041512
X-RAY DIFFRACTIONr_chiral_restr0.1110.2323
X-RAY DIFFRACTIONr_gen_planes_refined0.010.022938
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02549
LS refinement shellResolution: 1.8→1.847 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.243 124 -
Rwork0.207 2417 -
all-2541 -
obs--99.73 %

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