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- PDB-4r7i: Crystal structure of FMS kinase domain with a small molecular inh... -

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Basic information

Entry
Database: PDB / ID: 4r7i
TitleCrystal structure of FMS kinase domain with a small molecular inhibitor, GLEEVEC
ComponentsMacrophage colony-stimulating factor 1 receptor
Keywordstransferase/transferase inhibitor / CSF-1-R / FMS proto-oncogene / C-FMS / CD115 antigen / kinase / ATP-binding / GLEEVEC / 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-STI / Macrophage colony-stimulating factor 1 receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.75 Å
AuthorsZhang, Y. / Zhang, C.
CitationJournal: N Engl J Med / Year: 2015
Title: Structure-Guided Blockade of CSF1R Kinase in Tenosynovial Giant-Cell Tumor.
Authors: Tap, W.D. / Wainberg, Z.A. / Anthony, S.P. / Ibrahim, P.N. / Zhang, C. / Healey, J.H. / Chmielowski, B. / Staddon, A.P. / Cohn, A.L. / Shapiro, G.I. / Keedy, V.L. / Singh, A.S. / Puzanov, I. ...Authors: Tap, W.D. / Wainberg, Z.A. / Anthony, S.P. / Ibrahim, P.N. / Zhang, C. / Healey, J.H. / Chmielowski, B. / Staddon, A.P. / Cohn, A.L. / Shapiro, G.I. / Keedy, V.L. / Singh, A.S. / Puzanov, I. / Kwak, E.L. / Wagner, A.J. / Von Hoff, D.D. / Weiss, G.J. / Ramanathan, R.K. / Zhang, J. / Habets, G. / Zhang, Y. / Burton, E.A. / Visor, G. / Sanftner, L. / Severson, P. / Nguyen, H. / Kim, M.J. / Marimuthu, A. / Tsang, G. / Shellooe, R. / Gee, C. / West, B.L. / Hirth, P. / Nolop, K. / van de Rijn, M. / Hsu, H.H. / Peterfy, C. / Lin, P.S. / Tong-Starksen, S. / Bollag, G.
History
DepositionAug 27, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 12, 2015Provider: repository / Type: Initial release
Revision 1.1Sep 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_ref_seq_dif / struct_site
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI ..._chem_comp.pdbx_synonyms / _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

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Assembly

Deposited unit
A: Macrophage colony-stimulating factor 1 receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,1342
Polymers38,6401
Non-polymers4941
Water99155
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
A: Macrophage colony-stimulating factor 1 receptor
hetero molecules

A: Macrophage colony-stimulating factor 1 receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)78,2684
Polymers77,2802
Non-polymers9872
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation7_556y,x,-z+11
Buried area4710 Å2
ΔGint-31 kcal/mol
Surface area25530 Å2
MethodPISA
Unit cell
Length a, b, c (Å)63.130, 63.130, 183.460
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 receptor / CSF-1-R / CSF-1R / M-CSF-R / Proto-oncogene c-Fms


Mass: 38640.176 Da / Num. of mol.: 1 / Fragment: FMS kinase domain with KID (UNP residues 538-919) / Mutation: C667T, C830S, C907T
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, receptor protein-tyrosine kinase
#2: Chemical ChemComp-STI / 4-(4-METHYL-PIPERAZIN-1-YLMETHYL)-N-[4-METHYL-3-(4-PYRIDIN-3-YL-PYRIMIDIN-2-YLAMINO)-PHENYL]-BENZAMIDE / STI-571 / IMATINIB


Mass: 493.603 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H31N7O / Comment: medication, inhibitor*YM
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 55 / 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: 2.37 Å3/Da / Density % sol: 48 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 20% PEG8K, 0.2M MGCL AND 0.1M TRIS, pH 7.5, VAPOR DIFFUSION, SITTING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL9-2 / Wavelength: 1.18076 Å
DetectorType: MARMOSAIC 325 mm CCD / Detector: CCD / Date: Jul 21, 2011
RadiationMonochromator: double crystal Monochromator / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.18076 Å / Relative weight: 1
ReflectionResolution: 2.3→52 Å / Num. obs: 17142

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Processing

Software
NameVersionClassification
Blu-Icedata collection
MOLREPphasing
PHENIX(phenix.refine: 1.7.3_928)refinement
MOSFLMdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 4HW7

4hw7


Resolution: 2.75→44.64 Å / SU ML: 0.35 / Phase error: 19.47 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2359 495 4.84 %RANDOM
Rwork0.2006 ---
all0.2024 10299 --
obs0.2024 10217 99.2 %-
Solvent computationShrinkage radii: 1.11 Å / VDW probe radii: 1.3 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 27.413 Å2 / ksol: 0.353 e/Å3
Displacement parameters
Baniso -1Baniso -2Baniso -3
1-4.0146 Å20 Å2-0 Å2
2--4.0146 Å2-0 Å2
3----8.0292 Å2
Refinement stepCycle: LAST / Resolution: 2.75→44.64 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2269 0 37 55 2361
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0032363
X-RAY DIFFRACTIONf_angle_d0.7463200
X-RAY DIFFRACTIONf_dihedral_angle_d13.179848
X-RAY DIFFRACTIONf_chiral_restr0.047347
X-RAY DIFFRACTIONf_plane_restr0.004406
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.75-3.02670.28511190.24842340X-RAY DIFFRACTION99
3.0267-3.46450.29291190.20652382X-RAY DIFFRACTION99
3.4645-4.36440.21931340.18132403X-RAY DIFFRACTION99
4.3644-44.64550.2121230.19832597X-RAY DIFFRACTION99
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)
10.6464-0.1709-0.44470.87880.20121.96480.0023-0.04690.01810.07420.0419-0.08430.11320.0458-0.03210.21520.026-0.02390.24840.00180.259636.283213.042182.9313
20.70720.16790.39330.02960.08360.21340.01080.1267-0.11310.0973-0.0578-0.04080.0445-0.0176-0.01210.57130.04150.14410.6750.13740.3838.872813.361275.6045
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain A and resid 567:914
2X-RAY DIFFRACTION2chain A and resid 1001

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