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- PDB-6t2w: Crystal structure of the CSF1R kinase domain with a dihydropurino... -

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Basic information

Entry
Database: PDB / ID: 6t2w
TitleCrystal structure of the CSF1R kinase domain with a dihydropurinone inhibitor (compound 4)
ComponentsMacrophage colony-stimulating factor 1 receptor
KeywordsTRANSFERASE / kinase fold / type I kinase inhibitor
Function / homology
Function and homology information


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 ...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 tyrosine phosphorylation of STAT protein / Other interleukin signaling / positive regulation of cell motility / positive regulation of macrophage chemotaxis / growth factor binding / cellular response to cytokine stimulus / positive regulation of protein tyrosine kinase activity / cytokine binding / monocyte differentiation / hemopoiesis / regulation of MAPK cascade / macrophage differentiation / Transcriptional Regulation by VENTX / positive regulation of chemokine production / osteoclast differentiation / axon guidance / response to ischemia / regulation of actin cytoskeleton organization / placental growth factor receptor activity / insulin receptor activity / vascular endothelial growth factor receptor activity / hepatocyte growth factor receptor activity / macrophage colony-stimulating factor receptor activity / platelet-derived growth factor alpha-receptor activity / platelet-derived growth factor beta-receptor activity / stem cell factor receptor activity / boss receptor activity / protein tyrosine kinase collagen receptor activity / brain-derived neurotrophic factor receptor activity / GPI-linked ephrin receptor activity / transmembrane-ephrin receptor activity / epidermal growth factor receptor activity / fibroblast growth factor receptor activity / insulin-like growth factor receptor activity / receptor protein-tyrosine kinase / peptidyl-tyrosine phosphorylation / cytokine-mediated signaling pathway / cell surface receptor protein tyrosine kinase signaling pathway / Signaling by CSF1 (M-CSF) in myeloid cells / regulation of cell shape / protein tyrosine kinase activity / protein autophosphorylation / protein phosphatase binding / histone H3Y41 kinase activity / histone H2AXY142 kinase activity / positive regulation of ERK1 and ERK2 cascade / cell population proliferation / positive regulation of protein phosphorylation / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor complex / positive regulation of cell migration / inflammatory response / 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 / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Ig-like domain profile. / Immunoglobulin-like domain / Phosphorylase Kinase; domain 1 / Immunoglobulin-like domain superfamily / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / 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-M9T / Macrophage colony-stimulating factor 1 receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.7 Å
AuthorsSchimpl, M. / Goldberg, F.W. / Finlay, M.R.V. / Ting, A.K.T. / Beattie, D. / Lamont, G.M. / Fallan, C. / Wrigley, G.L. / Howard, M.R. / Williamson, B. ...Schimpl, M. / Goldberg, F.W. / Finlay, M.R.V. / Ting, A.K.T. / Beattie, D. / Lamont, G.M. / Fallan, C. / Wrigley, G.L. / Howard, M.R. / Williamson, B. / Davies, B.R. / Cadogan, E.B. / Ramos-Montoya, A. / Dean, E.
CitationJournal: J.Med.Chem. / Year: 2020
Title: The Discovery of 7-Methyl-2-[(7-methyl[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino]-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one (AZD7648), a Potent and Selective DNA-Dependent Protein ...Title: The Discovery of 7-Methyl-2-[(7-methyl[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino]-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one (AZD7648), a Potent and Selective DNA-Dependent Protein Kinase (DNA-PK) Inhibitor.
Authors: Goldberg, F.W. / Finlay, M.R.V. / Ting, A.K.T. / Beattie, D. / Lamont, G.M. / Fallan, C. / Wrigley, G.L. / Schimpl, M. / Howard, M.R. / Williamson, B. / Vazquez-Chantada, M. / Barratt, D.G. ...Authors: Goldberg, F.W. / Finlay, M.R.V. / Ting, A.K.T. / Beattie, D. / Lamont, G.M. / Fallan, C. / Wrigley, G.L. / Schimpl, M. / Howard, M.R. / Williamson, B. / Vazquez-Chantada, M. / Barratt, D.G. / Davies, B.R. / Cadogan, E.B. / Ramos-Montoya, A. / Dean, E.
History
DepositionOct 9, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 1, 2020Provider: repository / Type: Initial release
Revision 1.1Jan 22, 2020Group: Database references / Category: citation / citation_author
Item: _citation.title / _citation.year / _citation_author.name
Revision 1.2Apr 22, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.3May 1, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)38,0956
Polymers37,3281
Non-polymers7685
Water4,216234
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area590 Å2
ΔGint-38 kcal/mol
Surface area14960 Å2
MethodPISA
Unit cell
Length a, b, c (Å)81.040, 81.040, 146.000
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-

SO4

21A-1185-

HOH

31A-1318-

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: 37327.785 Da / Num. of mol.: 1
Fragment: kinase domain (amino acids Q542-R919) with internal deletion of amino acids 697-740
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CSF1R, FMS / Cell line (production host): Hi5 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P07333, receptor protein-tyrosine kinase
#2: Chemical ChemComp-M9T / 2-[(4-methoxy-2-methyl-phenyl)amino]-7-methyl-9-(4-oxidanylcyclohexyl)purin-8-one


Mass: 383.444 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H25N5O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-SO4 / SULFATE ION


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


Mass: 18.015 Da / Num. of mol.: 234 / 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: 2.47 Å3/Da / Density % sol: 50.24 % / Description: triangular plates
Crystal growTemperature: 277 K / Method: vapor diffusion / pH: 5.5
Details: 16% PEG3350, 0.15 M Ammonium Sulfate, 0.1 M PCTP pH 5.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.97626 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Apr 8, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97626 Å / Relative weight: 1
ReflectionResolution: 1.7→50.59 Å / Num. obs: 38401 / % possible obs: 97.5 % / Redundancy: 4.1 % / Biso Wilson estimate: 22.75 Å2 / CC1/2: 0.996 / Rmerge(I) obs: 0.094 / Rpim(I) all: 0.048 / Rrim(I) all: 0.106 / Net I/σ(I): 6.8 / Num. measured all: 158955 / Scaling rejects: 168
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
1.7-1.741.90.478441623130.740.4010.6270.879.5
7.6-50.594.90.06821844430.9930.0340.0761999.7

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
XDSdata reduction
Aimless0.5.23data scaling
MOLREPphasing
BUSTER2.11.7refinement
PDB_EXTRACT3.25data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: unpublished

Resolution: 1.7→24.33 Å / Cor.coef. Fo:Fc: 0.957 / Cor.coef. Fo:Fc free: 0.952 / SU R Cruickshank DPI: 0.088 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.089 / SU Rfree Blow DPI: 0.085 / SU Rfree Cruickshank DPI: 0.084
RfactorNum. reflection% reflectionSelection details
Rfree0.187 1872 4.88 %RANDOM
Rwork0.166 ---
obs0.167 38379 97.5 %-
Displacement parametersBiso max: 106.48 Å2 / Biso mean: 28.09 Å2 / Biso min: 10.7 Å2
Baniso -1Baniso -2Baniso -3
1-3.4578 Å20 Å20 Å2
2--3.4578 Å20 Å2
3----6.9155 Å2
Refine analyzeLuzzati coordinate error obs: 0.21 Å
Refinement stepCycle: final / Resolution: 1.7→24.33 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2387 0 48 234 2669
Biso mean--30.62 37.06 -
Num. residues----304
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d840SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes410HARMONIC5
X-RAY DIFFRACTIONt_it2491HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion312SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact3026SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d2491HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg3379HARMONIC20.97
X-RAY DIFFRACTIONt_omega_torsion3.37
X-RAY DIFFRACTIONt_other_torsion16.05
LS refinement shellResolution: 1.7→1.72 Å / Rfactor Rfree error: 0 / Total num. of bins used: 50
RfactorNum. reflection% reflection
Rfree0.2524 47 6.12 %
Rwork0.2184 721 -
all0.2204 768 -
obs--75.32 %
Refinement TLS params.Method: refined / Origin x: 17.3442 Å / Origin y: 26.737 Å / Origin z: 0.7008 Å
111213212223313233
T-0.0418 Å20.0013 Å20.005 Å2--0.0394 Å20.0158 Å2---0.0516 Å2
L1.1799 °20.3327 °20.0762 °2-0.8259 °20.0961 °2--0.216 °2
S-0.0002 Å °-0.063 Å °-0.0274 Å °-0.0199 Å °-0.0024 Å °0.0793 Å °-0.0024 Å °-0.0148 Å °0.0026 Å °
Refinement TLS groupSelection details: { A|* }

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