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- PDB-3lcd: Inhibitor Bound to A DFG-In structure of the Kinase Domain of CSF-1R -

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Basic information

Entry
Database: PDB / ID: 3lcd
TitleInhibitor Bound to A DFG-In structure of the Kinase Domain of CSF-1R
ComponentsMacrophage colony-stimulating factor 1 receptor
KeywordsTRANSFERASE / Kinase CFMS CSF-1R CSF tyrosine-kinase colony stimulating factor 1 receptor / ATP-binding / Disulfide bond / Glycoprotein / Immunoglobulin domain / Kinase / Membrane / Nucleotide-binding / Phosphoprotein / Proto-oncogene / Receptor / Transmembrane / Tyrosine-protein kinase
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-BDY / Macrophage colony-stimulating factor 1 receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.5 Å
AuthorsKamtekar, S. / Day, J.E. / Reitz, B.A. / Mathis, K.J. / Meyers, M.J.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2010
Title: Structure-based drug design enables conversion of a DFG-in binding CSF-1R kinase inhibitor to a DFG-out binding mode
Authors: Meyers, M.J. / Pelc, M. / Kamtekar, S. / Day, J. / Poda, G.I. / Hall, M.K. / Michener, M.L. / Reitz, B.A. / Mathis, K.J. / Pierce, B.S. / Parikh, M.D. / Mischke, D.A. / Long, S.A. / Parlow, ...Authors: Meyers, M.J. / Pelc, M. / Kamtekar, S. / Day, J. / Poda, G.I. / Hall, M.K. / Michener, M.L. / Reitz, B.A. / Mathis, K.J. / Pierce, B.S. / Parikh, M.D. / Mischke, D.A. / Long, S.A. / Parlow, J.J. / Anderson, D.R. / Thorarensen, A.
History
DepositionJan 10, 2010Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 2, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Advisory / Version format compliance
Revision 1.2Jul 26, 2017Group: Data collection / Refinement description / Source and taxonomy
Category: diffrn_detector / entity_src_gen / software / Item: _diffrn_detector.detector

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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)38,0514
Polymers37,3341
Non-polymers7183
Water79344
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)57.649, 74.125, 91.024
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121
DetailsThe kinase domain fragment is monomeric

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Components

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


Mass: 37333.754 Da / Num. of mol.: 1 / Fragment: Kinase Domain / Mutation: KID domain replaced by linker
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CSF-1R, CSF1R, FMS / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P07333, receptor protein-tyrosine kinase
#2: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-BDY / N~3~-(2,6-dichlorobenzyl)-5-(4-{[(2R)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]carbonyl}phenyl)pyrazine-2,3-diamine


Mass: 525.473 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H30Cl2N6O
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 44 / 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: 2.6 Å3/Da / Density % sol: 52.78 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 5.5
Details: Equal volumes of protein:ligand (10 mg/ml protein, 1 mM ligand, 200 mM NaCl, 50 mM Potassium dihydrogen phosphate pH 7.5, 5% glycerol, 0.25 mM TCEP) and well solution (0.1 M sodium acetate ...Details: Equal volumes of protein:ligand (10 mg/ml protein, 1 mM ligand, 200 mM NaCl, 50 mM Potassium dihydrogen phosphate pH 7.5, 5% glycerol, 0.25 mM TCEP) and well solution (0.1 M sodium acetate pH 5.5, 0.2 M Lithium sulfate, 5 mM DTT, 1.5% glycerol, 10-25% PEG 3350) were mixed and set up., VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-F / Wavelength: 1.07804 Å
DetectorType: MAR scanner 300 mm plate / Detector: IMAGE PLATE / Date: Mar 18, 2009
RadiationMonochromator: Diamond [111] / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.07804 Å / Relative weight: 1
ReflectionResolution: 2.5→20 Å / Num. all: 13960 / Num. obs: 13462 / % possible obs: 96.7 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -3 / Redundancy: 5.65 % / Biso Wilson estimate: 44.5 Å2 / Rsym value: 0.143 / Net I/σ(I): 11.5
Reflection shellResolution: 2.5→2.59 Å / Redundancy: 2.8 % / Mean I/σ(I) obs: 2.1 / Num. unique all: 1062 / Rsym value: 0.504 / % possible all: 78.6

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Processing

Software
NameVersionClassification
HKL-2000data collection
PHASERphasing
REFMAC5.5.0102refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.5→20 Å / Cor.coef. Fo:Fc: 0.928 / Cor.coef. Fo:Fc free: 0.903 / SU B: 21.149 / SU ML: 0.223 / TLS residual ADP flag: LIKELY RESIDUAL / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.461 / ESU R Free: 0.292 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.26497 662 4.9 %RANDOM
Rwork0.21592 ---
all0.2183 13462 --
obs0.2183 12800 96.37 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 14.703 Å2
Baniso -1Baniso -2Baniso -3
1-0.85 Å20 Å20 Å2
2--2.62 Å20 Å2
3----3.46 Å2
Refine analyzeLuzzati coordinate error obs: 0.3759 Å
Refinement stepCycle: LAST / Resolution: 2.5→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2249 0 46 44 2339
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0222356
X-RAY DIFFRACTIONr_bond_other_d0.0010.021525
X-RAY DIFFRACTIONr_angle_refined_deg1.1731.9743200
X-RAY DIFFRACTIONr_angle_other_deg0.80433735
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.8715289
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.03224.804102
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.8715379
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.934158
X-RAY DIFFRACTIONr_chiral_restr0.0640.2349
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0212645
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02458
X-RAY DIFFRACTIONr_mcbond_it0.4121.51442
X-RAY DIFFRACTIONr_mcbond_other0.061.5588
X-RAY DIFFRACTIONr_mcangle_it0.78322305
X-RAY DIFFRACTIONr_scbond_it1.0783914
X-RAY DIFFRACTIONr_scangle_it1.7824.5894
LS refinement shellResolution: 2.504→2.569 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.336 41 -
Rwork0.281 720 -
obs--75.57 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°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)
11.46131.20061.04834.00931.50093.8283-0.09110.05170.2421-0.2627-0.03380.3366-0.2122-0.08960.12490.11430.0267-0.02770.20140.01730.1161-17.863615.2414-18.2073
23.27790.49-1.17422.30650.35194.1515-0.0284-0.0076-0.0472-0.0115-0.04140.12520.20260.0840.06980.05450.019-0.02690.0657-0.01350.0268-25.40380.00350.1204
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A560 - 665
2X-RAY DIFFRACTION2A666 - 930

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