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- PDB-4hw7: Crystal structure of FMS kinase domain with a small molecular inh... -

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Basic information

Entry
Database: PDB / ID: 4hw7
TitleCrystal structure of FMS kinase domain with a small molecular inhibitor, PLX647-OME
ComponentsMacrophage colony-stimulating factor 1 receptor
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / CSF-1-R / FMS PROTO-ONCOGENE / C-FMS / CD115 antigen / Kinase / ATP-binding / TRANSFERASE-TRANSFERASE INHIBITOR complex
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 / Other interleukin signaling / positive regulation of tyrosine phosphorylation of STAT protein / positive regulation of cell motility / positive regulation of protein tyrosine kinase activity / growth factor binding / positive regulation of macrophage chemotaxis / cellular response to cytokine stimulus / cytokine binding / hemopoiesis / regulation of MAPK cascade / monocyte differentiation / macrophage differentiation / Transcriptional Regulation by VENTX / positive regulation of chemokine production / osteoclast differentiation / axon guidance / cell surface receptor protein tyrosine kinase signaling pathway / 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 / transmembrane-ephrin receptor activity / GPI-linked ephrin receptor activity / epidermal growth factor receptor activity / fibroblast growth factor receptor activity / cytokine-mediated signaling pathway / insulin-like growth factor receptor activity / receptor protein-tyrosine kinase / peptidyl-tyrosine phosphorylation / Signaling by CSF1 (M-CSF) in myeloid cells / cell migration / regulation of cell shape / positive regulation of protein phosphorylation / protein autophosphorylation / protein tyrosine kinase activity / protein phosphatase binding / cell population proliferation / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor complex / positive regulation of ERK1 and ERK2 cascade / positive regulation of cell migration / inflammatory response / negative regulation of cell population proliferation / innate immune response / intracellular membrane-bounded organelle / 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. / Tyrosine-protein kinase, active site / Immunoglobulin subtype / Immunoglobulin / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Phosphorylase Kinase; domain 1 / Ig-like domain profile. / Immunoglobulin-like domain / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Immunoglobulin-like domain superfamily / 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-64M / Macrophage colony-stimulating factor 1 receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.9001 Å
AuthorsZhang, Y. / Zhang, C.
CitationJournal: Proc.Natl.Acad.Sci.USA / Year: 2013
Title: Design and pharmacology of a highly specific dual FMS and KIT kinase inhibitor.
Authors: Zhang, C. / Ibrahim, P.N. / Zhang, J. / Burton, E.A. / Habets, G. / Zhang, Y. / Powell, B. / West, B.L. / Matusow, B. / Tsang, G. / Shellooe, R. / Carias, H. / Nguyen, H. / Marimuthu, A. / ...Authors: Zhang, C. / Ibrahim, P.N. / Zhang, J. / Burton, E.A. / Habets, G. / Zhang, Y. / Powell, B. / West, B.L. / Matusow, B. / Tsang, G. / Shellooe, R. / Carias, H. / Nguyen, H. / Marimuthu, A. / Zhang, K.Y. / Oh, A. / Bremer, R. / Hurt, C.R. / Artis, D.R. / Wu, G. / Nespi, M. / Spevak, W. / Lin, P. / Nolop, K. / Hirth, P. / Tesch, G.H. / Bollag, G.
History
DepositionNov 7, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 27, 2013Provider: repository / Type: Initial release
Revision 1.1Apr 17, 2013Group: Database references
Revision 1.2Feb 28, 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

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)39,0532
Polymers38,6401
Non-polymers4121
Water00
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)78,1054
Polymers77,2802
Non-polymers8252
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation7_556y,x,-z+11
Buried area1960 Å2
ΔGint-12 kcal/mol
Surface area26090 Å2
MethodPISA
Unit cell
Length a, b, c (Å)62.964, 62.964, 182.780
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 / Mutation: C667T, C830S, C907T
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CSF1R, FMS / Cell line (production host): SF9 / Production host: SPODOPTERA FRUGIPERDA (fall armyworm)
References: UniProt: P07333, receptor protein-tyrosine kinase
#2: Chemical ChemComp-64M / 5-[(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-N-[4-(trifluoromethyl)benzyl]pyridin-2-amine


Mass: 412.408 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H19F3N4O

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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: 2.35 Å3/Da / Density % sol: 47.59 %
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: ALS / Beamline: 8.3.1 / Wavelength: 1.1159 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Aug 11, 2012
RadiationMonochromator: Double flat crystal, Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.1159 Å / Relative weight: 1
ReflectionResolution: 2.9→59.5 Å / Num. all: 8769 / Num. obs: 8735 / % possible obs: 99.6 % / Observed criterion σ(F): -3 / Observed criterion σ(I): -3
Reflection shellResolution: 2.9→3.06 Å / % possible all: 99.8

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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 / Resolution: 2.9001→51.9 Å / SU ML: 0.52 / σ(F): 1.36 / Phase error: 26.97 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.267 414 4.75 %RANDOM
Rwork0.22 ---
all0.222 8769 --
obs0.222 8714 99.38 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 40.606 Å2 / ksol: 0.357 e/Å3
Displacement parameters
Baniso -1Baniso -2Baniso -3
1-10.2841 Å20 Å2-0 Å2
2--10.2841 Å2-0 Å2
3----20.5683 Å2
Refinement stepCycle: LAST / Resolution: 2.9001→51.9 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2262 0 30 0 2292
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0052349
X-RAY DIFFRACTIONf_angle_d0.8913183
X-RAY DIFFRACTIONf_dihedral_angle_d14.038847
X-RAY DIFFRACTIONf_chiral_restr0.057345
X-RAY DIFFRACTIONf_plane_restr0.005404
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.9001-3.31960.38851370.29942690X-RAY DIFFRACTION99
3.3196-4.18210.27931350.21912728X-RAY DIFFRACTION100
4.1821-51.85790.21931420.1932882X-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)
11.5689-1.1011-1.06361.69570.21137.5040.134-0.06250.1119-0.0227-0.0516-0.17160.09890.3495-0.08890.2567-0.0402-0.06770.2945-0.01210.390636.412212.832282.4986
20.4707-0.16970.56060.2164-0.24640.68170.05850.03670.0222-0.08990.1604-0.0276-0.0112-0.1175-0.18371.05990.06730.11871.25250.23310.767336.503212.084874.8879
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain A and resid 566:914
2X-RAY DIFFRACTION2chain A and resid 1001:1001

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