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- PDB-7mfc: Crystal structure of CSF1R in complex with vimseltinib -

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Basic information

Entry
Database: PDB / ID: 7mfc
TitleCrystal structure of CSF1R in complex with vimseltinib
ComponentsMacrophage colony-stimulating factor 1 receptor
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / cancer / 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 / cytokine binding / growth factor binding / cellular response to cytokine stimulus / 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 / response to ischemia / regulation of actin cytoskeleton organization / axon guidance / 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 phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of ERK1 and ERK2 cascade / 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 / Tyrosine 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 / 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
Similarity search - Domain/homology
Vimseltinib / Macrophage colony-stimulating factor 1 receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.8 Å
AuthorsAbendroth, J. / Davies, D.R. / Atkins, K.
CitationJournal: Mol.Cancer Ther. / Year: 2021
Title: Vimseltinib: A Precision CSF1R Therapy for Tenosynovial Giant Cell Tumors and Diseases Promoted by Macrophages.
Authors: Smith, B.D. / Kaufman, M.D. / Wise, S.C. / Ahn, Y.M. / Caldwell, T.M. / Leary, C.B. / Lu, W.P. / Tan, G. / Vogeti, L. / Vogeti, S. / Wilky, B.A. / Davis, L.E. / Sharma, M. / Ruiz-Soto, R. / Flynn, D.L.
History
DepositionApr 8, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 24, 2021Provider: repository / Type: Initial release
Revision 1.1Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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)39,0722
Polymers38,6401
Non-polymers4311
Water25214
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)61.870, 61.870, 181.750
Angle α, β, γ (deg.)90.000, 90.000, 90.000
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: Kinase domain, UNP residues 542-919 with deletion of 696-741
Mutation: C677T, C830S, C907T
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CSF1R, FMS / Plasmid: CID100239 / Production host: Trichoplusia ni (cabbage looper) / Strain (production host): TNI
References: UniProt: P07333, receptor protein-tyrosine kinase
#2: Chemical ChemComp-Z6V / Vimseltinib / 3-methyl-5-(6-methyl-5-{[2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl]oxy}pyridin-2-yl)-2-[(propan-2-yl)amino]pyrimidin-4(3H)-one


Mass: 431.490 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H25N7O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 14 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.25 Å3/Da / Density % sol: 45 %
Crystal growTemperature: 289 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: CSF1R at 4mg/ml with 0.5mM vimseltinib: Crystallization: 100mM Tris base / HCl pH 7.71, 18% PEG 8000, 100mM MgCl2: Cryo: 20% glycerol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-F / Wavelength: 0.97872 Å
DetectorType: RAYONIX MX-300 / Detector: CCD / Date: Oct 13, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97872 Å / Relative weight: 1
ReflectionResolution: 2.8→45.44 Å / Num. obs: 9256 / % possible obs: 99.3 % / Redundancy: 6.4 % / Biso Wilson estimate: 45.34 Å2 / CC1/2: 0.996 / Rmerge(I) obs: 0.128 / Rrim(I) all: 0.139 / Χ2: 0.918 / Net I/σ(I): 10.94 / Num. measured all: 59674
Reflection shellResolution: 2.8→2.877 Å / Redundancy: 6.9 % / Rmerge(I) obs: 0.534 / Mean I/σ(I) obs: 3.23 / Num. unique obs: 123 / CC1/2: 0.998 / Rrim(I) all: 0.047 / % possible all: 100

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
PHENIX1.11_2563refinement
XDSdata reduction
XSCALEVERSION May 1, 2016 BUILT=20160617data scaling
PHASERphasing
PDB_EXTRACT3.27data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2I1M CHAIN A

2i1m


Resolution: 2.8→45.44 Å / SU ML: 0.34 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 27.67 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.256 889 9.64 %RANDOM, 0
Rwork0.226 ---
obs0.229 9224 98.9 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 140.98 Å2 / Biso mean: 53.81 Å2 / Biso min: 15.18 Å2
Refinement stepCycle: final / Resolution: 2.8→45.44 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2157 0 32 15 2204
Biso mean--43.14 38.43 -
Num. residues----287
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0032243
X-RAY DIFFRACTIONf_angle_d0.5843058
X-RAY DIFFRACTIONf_chiral_restr0.044339
X-RAY DIFFRACTIONf_plane_restr0.006394
X-RAY DIFFRACTIONf_dihedral_angle_d16.9021299
LS refinement shellResolution: 2.8→2.98 Å / Rfactor Rfree error: 0 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.3688 144 -
Rwork0.2997 1348 -
all-1492 -
obs--100 %
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)
14.48540.4299-0.05216.15640.51145.21130.0420.3478-0.1298-0.1848-0.10740.40740.1614-0.7704-0.00210.39510.01330.00560.51330.0410.326321.1954-12.6176-25.1645
21.6385-0.2958-0.28111.7223-0.13232.37520.1129-0.118-0.074-0.0137-0.0060.0071-0.0765-0.2496-0.10280.3263-0.0753-0.00450.33550.03440.29128.6106-12.3605-1.5033
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A613 - 706
2X-RAY DIFFRACTION2A706 - 913

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