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- PDB-3bea: cFMS tyrosine kinase (tie2 KID) in complex with a pyrimidinopyrid... -

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Basic information

Entry
Database: PDB / ID: 3bea
TitlecFMS tyrosine kinase (tie2 KID) in complex with a pyrimidinopyridone inhibitor
ComponentsMacrophage colony-stimulating factor 1 receptor
KeywordsTRANSFERASE / Kinase domain / inhibitor / juxtamembrane domain / ATP-binding / Glycoprotein / Immunoglobulin domain / Nucleotide-binding / Phosphoprotein / Polymorphism / Proto-oncogene / Receptor / Transmembrane / Tyrosine-protein kinase
Function / homology
Function and homology information


Tie signaling pathway / glomerulus vasculature development / regulation of establishment or maintenance of cell polarity / macrophage colony-stimulating factor receptor activity / forebrain neuron differentiation / CSF1-CSF1R complex / macrophage colony-stimulating factor signaling pathway / cell-cell junction maintenance / regulation of endothelial cell apoptotic process / regulation of macrophage migration ...Tie signaling pathway / glomerulus vasculature development / regulation of establishment or maintenance of cell polarity / macrophage colony-stimulating factor receptor activity / forebrain neuron differentiation / CSF1-CSF1R complex / macrophage colony-stimulating factor signaling pathway / cell-cell junction maintenance / regulation of endothelial cell apoptotic process / regulation of macrophage migration / cellular response to macrophage colony-stimulating factor stimulus / microglial cell proliferation / regulation of vascular permeability / olfactory bulb development / mammary gland duct morphogenesis / endochondral ossification / positive regulation by host of viral process / heart trabecula formation / ruffle organization / definitive hemopoiesis / positive regulation of macrophage proliferation / regulation of bone resorption / positive regulation of cell motility / sprouting angiogenesis / endothelial cell proliferation / positive regulation of intracellular signal transduction / Other interleukin signaling / positive regulation of Rho protein signal transduction / positive regulation of macrophage chemotaxis / cytokine binding / positive regulation of Rac protein signal transduction / growth factor binding / cellular response to cytokine stimulus / positive regulation of focal adhesion assembly / monocyte differentiation / microvillus / regulation of MAPK cascade / macrophage differentiation / hemopoiesis / positive regulation of protein tyrosine kinase activity / centriolar satellite / Transcriptional Regulation by VENTX / negative regulation of endothelial cell apoptotic process / positive regulation of chemokine production / positive regulation of tyrosine phosphorylation of STAT protein / Tie2 Signaling / response to cAMP / cell surface receptor protein tyrosine kinase signaling pathway / positive regulation of endothelial cell proliferation / positive regulation of endothelial cell migration / transmembrane receptor protein tyrosine kinase activity / negative regulation of angiogenesis / substrate adhesion-dependent cell spreading / osteoclast differentiation / basal plasma membrane / response to ischemia / regulation of actin cytoskeleton organization / axon guidance / receptor protein-tyrosine kinase / response to peptide hormone / cytokine-mediated signaling pathway / negative regulation of inflammatory response / response to estrogen / peptidyl-tyrosine phosphorylation / positive regulation of angiogenesis / Signaling by CSF1 (M-CSF) in myeloid cells / cell-cell junction / cell-cell signaling / signaling receptor activity / heart development / regulation of cell shape / RAF/MAP kinase cascade / basolateral plasma membrane / protein phosphatase binding / protein tyrosine kinase activity / angiogenesis / cell population proliferation / positive regulation of MAPK cascade / protein autophosphorylation / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of ERK1 and ERK2 cascade / receptor complex / response to hypoxia / protein kinase activity / positive regulation of cell migration / inflammatory response / positive regulation of protein phosphorylation / membrane raft / apical plasma membrane / phosphorylation / negative regulation of cell population proliferation / intracellular membrane-bounded organelle / innate immune response / focal adhesion / positive regulation of cell population proliferation / negative regulation of apoptotic process / cell surface / signal transduction / protein homodimerization activity / extracellular region
Similarity search - Function
Tyrosine-protein kinase, receptor Tie-2, Ig-like domain 1, N-terminal / Tie-2 Ig-like domain 1 / Macrophage colony-stimulating factor 1 receptor / Laminin-type EGF domain / Tyrosine-protein kinase, receptor class III, conserved site / Receptor tyrosine kinase class III signature. / Immunoglobulin / Immunoglobulin domain / Immunoglobulin domain / Epidermal growth factor-like domain. ...Tyrosine-protein kinase, receptor Tie-2, Ig-like domain 1, N-terminal / Tie-2 Ig-like domain 1 / Macrophage colony-stimulating factor 1 receptor / Laminin-type EGF domain / Tyrosine-protein kinase, receptor class III, conserved site / Receptor tyrosine kinase class III signature. / Immunoglobulin / Immunoglobulin domain / Immunoglobulin domain / Epidermal growth factor-like domain. / EGF-like domain profile. / EGF-like domain signature 2. / EGF-like domain signature 1. / Fibronectin type III domain / EGF-like domain / Fibronectin type 3 domain / Immunoglobulin subtype 2 / Immunoglobulin C-2 Type / Fibronectin type-III domain profile. / Fibronectin type III / Fibronectin type III superfamily / 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 / Serine/Threonine protein kinases, catalytic domain / 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-IXH / Macrophage colony-stimulating factor 1 receptor / Angiopoietin-1 receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.02 Å
AuthorsSchubert, C.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2008
Title: Design and synthesis of a pyrido[2,3-d]pyrimidin-5-one class of anti-inflammatory FMS inhibitors.
Authors: Huang, H. / Hutta, D.A. / Hu, H. / DesJarlais, R.L. / Schubert, C. / Petrounia, I.P. / Chaikin, M.A. / Manthey, C.L. / Player, M.R.
History
DepositionNov 16, 2007Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 15, 2008Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Aug 2, 2017Group: Source and taxonomy / Category: entity_src_gen
Revision 1.3Oct 20, 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 1.4Aug 30, 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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,4535
Polymers37,6551
Non-polymers7984
Water3,045169
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)81.140, 81.140, 145.650
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-1079-

HOH

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Components

#1: Protein Macrophage colony-stimulating factor 1 receptor / CSF-1-R / Fms proto-oncogene / c-fms / CD115 antigen


Mass: 37655.148 Da / Num. of mol.: 1 / Mutation: A695L
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CSF1R, FMS / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P07333, UniProt: Q02763, 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-IXH / 8-(2,3-dihydro-1H-inden-5-yl)-2-({4-[(3R,5S)-3,5-dimethylpiperazin-1-yl]phenyl}amino)-5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide


Mass: 509.602 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H31N7O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 169 / 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: 2.45 Å3/Da / Density % sol: 49.8 %
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-BM / Wavelength: 1 Å
DetectorType: MAR CCD 165 mm / Detector: CCD / Date: Jul 14, 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: 2.02→31.13 Å / Num. all: 24175 / Num. obs: 20630 / % possible obs: 87.9 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -3 / Redundancy: 3.2 % / Biso Wilson estimate: 16.7 Å2 / Rmerge(I) obs: 0.062 / Net I/σ(I): 17.7
Reflection shellResolution: 2.02→2.09 Å / Redundancy: 2 % / Rmerge(I) obs: 0.23 / Mean I/σ(I) obs: 3.4 / Num. unique all: 1226 / % possible all: 52.3

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Processing

Software
NameVersionClassification
CNX2005refinement
DENZOdata reduction
SCALEPACKdata scaling
CNX2005phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: pdb entry 2i1m

2i1m


Resolution: 2.02→31.13 Å / Rfactor Rfree error: 0.006 / Data cutoff high absF: 2313407.9 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.23 1514 7.3 %RANDOM
Rwork0.193 ---
all-24175 --
obs-20630 88.2 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 45.8659 Å2 / ksol: 0.363415 e/Å3
Displacement parametersBiso mean: 30 Å2
Baniso -1Baniso -2Baniso -3
1--3.18 Å2-0.69 Å20 Å2
2---3.18 Å20 Å2
3---6.36 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.27 Å0.22 Å
Luzzati d res low-5 Å
Luzzati sigma a0.15 Å0.15 Å
Refinement stepCycle: LAST / Resolution: 2.02→31.13 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2461 0 53 169 2683
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.005
X-RAY DIFFRACTIONc_bond_d_na
X-RAY DIFFRACTIONc_bond_d_prot
X-RAY DIFFRACTIONc_angle_d
X-RAY DIFFRACTIONc_angle_d_na
X-RAY DIFFRACTIONc_angle_d_prot
X-RAY DIFFRACTIONc_angle_deg0.8
X-RAY DIFFRACTIONc_angle_deg_na
X-RAY DIFFRACTIONc_angle_deg_prot
X-RAY DIFFRACTIONc_dihedral_angle_d20.8
X-RAY DIFFRACTIONc_dihedral_angle_d_na
X-RAY DIFFRACTIONc_dihedral_angle_d_prot
X-RAY DIFFRACTIONc_improper_angle_d0.68
X-RAY DIFFRACTIONc_improper_angle_d_na
X-RAY DIFFRACTIONc_improper_angle_d_prot
X-RAY DIFFRACTIONc_mcbond_it1.561.5
X-RAY DIFFRACTIONc_mcangle_it2.492
X-RAY DIFFRACTIONc_scbond_it2.112
X-RAY DIFFRACTIONc_scangle_it3.052.5
LS refinement shellResolution: 2.02→2.13 Å / Rfactor Rfree error: 0.022 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.249 125 6.3 %
Rwork0.22 1860 -
obs-1860 49.2 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1protein_rep.paramprotein.top
X-RAY DIFFRACTION2inh.parinh.top
X-RAY DIFFRACTION3water_rep.paramwater.top
X-RAY DIFFRACTION4ion.paramion.top

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