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

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Basic information

Entry
Database: PDB / ID: 3lco
TitleInhibitor Bound to A DFG-Out structure of the Kinase Domain of CSF-1R
ComponentsMacrophage colony-stimulating factor 1 receptor
KeywordsTRANSFERASE / 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-LC0 / Macrophage colony-stimulating factor 1 receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.4 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 11, 2010Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 15, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Aug 16, 2017Group: Refinement description / Source and taxonomy / Category: entity_src_gen / software
Revision 1.3Feb 21, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / 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

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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)36,7292
Polymers36,2811
Non-polymers4481
Water00
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)62.916, 62.916, 183.943
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number96
Space group name H-MP43212

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Components

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


Mass: 36280.562 Da / Num. of mol.: 1 / Fragment: Kinase Domain
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-LC0 / 3-({4-methoxy-5-[(4-methoxybenzyl)oxy]pyridin-2-yl}methoxy)-5-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-amine


Mass: 448.474 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H24N6O4

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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: 2.51 Å3/Da / Density % sol: 50.97 %
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop / pH: 8.5
Details: 11 mg/mL protein incubated with 4 mM inhibitor at 4C overnight followed by addition of 1 ug Arg-C (per 50 ul sample) at 22C for 24 hours, followed by addition of 0.5 uL of 5 mg/mL leupeptin, ...Details: 11 mg/mL protein incubated with 4 mM inhibitor at 4C overnight followed by addition of 1 ug Arg-C (per 50 ul sample) at 22C for 24 hours, followed by addition of 0.5 uL of 5 mg/mL leupeptin, followed by mixing with equal volumes of well solution:22.5-35% PEG 4000, 0.1M Tris-HCL pH 8.5, 0.2M MgCl2, VAPOR DIFFUSION, HANGING DROP, temperature 295K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-D / Wavelength: 1.07816 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Apr 9, 2009
RadiationMonochromator: Diamond [111] / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.07816 Å / Relative weight: 1
ReflectionResolution: 3.4→20 Å / Num. all: 5300 / Num. obs: 5285 / % possible obs: 95.2 % / Observed criterion σ(I): -3 / Redundancy: 3.2 % / Biso Wilson estimate: 68 Å2 / Rsym value: 0.156 / Net I/σ(I): 8
Reflection shellResolution: 3.4→3.52 Å / Redundancy: 3.3 % / Mean I/σ(I) obs: 1.9 / Num. unique all: 536 / Rsym value: 0.579 / % possible all: 98.5

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Processing

Software
NameVersionClassification
HKL-2000data collection
REFMACrigid body refinementrefinement
HKL-2000data reduction
HKL-2000data scaling
REFMACrigid body refinementphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 3.4→19.9 Å / Cor.coef. Fo:Fc: 0.896 / Cor.coef. Fo:Fc free: 0.831 / SU B: 74.386 / SU ML: 0.55 / Isotropic thermal model: Isotropic / Cross valid method: THROUGHOUT / σ(F): 0 / σ(I): -3 / ESU R Free: 0.683 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.28882 250 4.7 %RANDOM
Rwork0.24518 ---
all0.247 5300 --
obs0.24721 5035 95.59 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 62.589 Å2
Baniso -1Baniso -2Baniso -3
1-1.2 Å20 Å20 Å2
2--1.2 Å20 Å2
3----2.4 Å2
Refinement stepCycle: LAST / Resolution: 3.4→19.9 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2252 0 33 0 2285
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0040.0222345
X-RAY DIFFRACTIONr_bond_other_d0.0010.021528
X-RAY DIFFRACTIONr_angle_refined_deg0.7131.973184
X-RAY DIFFRACTIONr_angle_other_deg0.72133729
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.1635291
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.01724.02197
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.46315368
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.6131510
X-RAY DIFFRACTIONr_chiral_restr0.0410.2351
X-RAY DIFFRACTIONr_gen_planes_refined0.0020.0212657
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02472
X-RAY DIFFRACTIONr_mcbond_it0.0381.51457
X-RAY DIFFRACTIONr_mcbond_other0.0041.5593
X-RAY DIFFRACTIONr_mcangle_it0.07222322
X-RAY DIFFRACTIONr_scbond_it0.0723888
X-RAY DIFFRACTIONr_scangle_it0.1284.5861
LS refinement shellResolution: 3.401→3.487 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.329 23 -
Rwork0.299 364 -
obs--97.48 %
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)
14.2510.3291-1.88515.23142.65529.1652-0.1920.0617-0.46930.0983-0.22290.54050.5852-0.76680.41480.24690.02260.06460.1689-0.00850.1808-11.08218.6335-24.2707
25.5562-0.42380.44122.53540.33672.98640.04220.2593-0.3259-0.2828-0.0905-0.07750.1455-0.12740.04830.1361-0.0253-0.00450.0283-0.01040.0332-2.994719.0589-0.7959
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A550 - 665
2X-RAY DIFFRACTION2A666 - 930

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