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- PDB-4r7h: Crystal structure of FMS KINASE domain with a small molecular inh... -

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Basic information

Entry
Database: PDB / ID: 4r7h
TitleCrystal structure of FMS KINASE domain with a small molecular inhibitor, PLX3397
ComponentsMacrophage colony-stimulating factor 1 receptor
Keywordstransferase/transferase inhibitor / CSF-1-R / FMS proto-oncogene / C-FMS / CD115 antigen / kinase / ATP-binding / PLX3397 / 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-P31 / Macrophage colony-stimulating factor 1 receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.8001 Å
AuthorsZhang, Y. / Zhang, K. / 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
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / 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)39,0582
Polymers38,6401
Non-polymers4181
Water77543
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)78,1164
Polymers77,2802
Non-polymers8362
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation7_555y,x,-z1
Buried area2300 Å2
ΔGint-16 kcal/mol
Surface area25900 Å2
MethodPISA
Unit cell
Length a, b, c (Å)63.984, 63.984, 185.041
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-P31 / 5-[(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-N-{[6-(trifluoromethyl)pyridin-3-yl]methyl}pyridin-2-amine


Mass: 417.815 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H15ClF3N5 / Comment: inhibitor*YM
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 43 / 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: 2.45 Å3/Da / Density % sol: 49.81 %
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: 1.11587 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Nov 25, 2008
RadiationMonochromator: Double flat crystal, Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.11587 Å / Relative weight: 1
ReflectionResolution: 2.8→60.471 Å / Num. all: 10121 / Num. obs: 10071

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Processing

Software
NameVersionClassification
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: 2.8001→52.625 Å / SU ML: 0.35 / σ(F): 1.74 / Phase error: 21.72 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2481 506 5.02 %RANDOM
Rwork0.2208 ---
obs0.2222 10071 99.52 %-
all-10121 --
Solvent computationShrinkage radii: 0.73 Å / VDW probe radii: 1 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 24.59 Å2 / ksol: 0.379 e/Å3
Displacement parameters
Baniso -1Baniso -2Baniso -3
1--0.7333 Å20 Å20 Å2
2---0.7333 Å20 Å2
3---1.4665 Å2
Refinement stepCycle: LAST / Resolution: 2.8001→52.625 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2428 0 29 43 2500
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0042518
X-RAY DIFFRACTIONf_angle_d0.7273413
X-RAY DIFFRACTIONf_dihedral_angle_d13.685907
X-RAY DIFFRACTIONf_chiral_restr0.051370
X-RAY DIFFRACTIONf_plane_restr0.003432
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.8001-3.08180.29071350.27272296X-RAY DIFFRACTION99
3.0818-3.52770.31791170.23392334X-RAY DIFFRACTION100
3.5277-4.44410.18731270.19742388X-RAY DIFFRACTION100
4.4441-52.63470.25261270.21422547X-RAY DIFFRACTION100

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