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- PDB-6n33: Crystal structure of fms kinase domain with a small molecular inh... -

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Basic information

Entry
Database: PDB / ID: 6n33
TitleCrystal structure of fms kinase domain with a small molecular inhibitor, PLX5622
ComponentsMacrophage colony-stimulating factor 1 receptor
KeywordsTRANSFERASE / CSF-1-R / FMS PROTO-ONCOGENE / C-FMS / CD115 ANTIGEN / KINASE / ATP-BINDING / PLX5622 / 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 / 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-622 / Macrophage colony-stimulating factor 1 receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.25 Å
AuthorsZhang, Y.
CitationJournal: Nat Commun / Year: 2019
Title: Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer's disease model.
Authors: Spangenberg, E. / Severson, P.L. / Hohsfield, L.A. / Crapser, J. / Zhang, J. / Burton, E.A. / Zhang, Y. / Spevak, W. / Lin, J. / Phan, N.Y. / Habets, G. / Rymar, A. / Tsang, G. / Walters, J. ...Authors: Spangenberg, E. / Severson, P.L. / Hohsfield, L.A. / Crapser, J. / Zhang, J. / Burton, E.A. / Zhang, Y. / Spevak, W. / Lin, J. / Phan, N.Y. / Habets, G. / Rymar, A. / Tsang, G. / Walters, J. / Nespi, M. / Singh, P. / Broome, S. / Ibrahim, P. / Zhang, C. / Bollag, G. / West, B.L. / Green, K.N.
History
DepositionNov 14, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 18, 2019Provider: repository / Type: Initial release
Revision 1.1Oct 11, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)39,0362
Polymers38,6401
Non-polymers3951
Water2,396133
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)62.620, 62.620, 182.369
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number96
Space group name H-MP43212
Components on special symmetry positions
IDModelComponents
11A-1227-

HOH

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Components

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


Mass: 38640.176 Da / Num. of mol.: 1 / 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-622 / 6-fluoro-N-[(5-fluoro-2-methoxypyridin-3-yl)methyl]-5-[(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]pyridin-2-amine


Mass: 395.405 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H19F2N5O / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 133 / 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: 2.31 Å3/Da / Density % sol: 46.83 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / Details: 20% PEG8K, 0.2M MGCL2 AND 0.1M TRIS, PH 7.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 8.3.1 / Wavelength: 1.11587 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Dec 21, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.11587 Å / Relative weight: 1
ReflectionResolution: 2.25→59.3 Å / Num. obs: 18091 / % possible obs: 99.9 % / Redundancy: 8.3 % / Net I/σ(I): 6.9
Reflection shellResolution: 2.25→2.37 Å

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Processing

Software
NameVersionClassification
PHENIX(1.11.1_2575: ???)refinement
MOSFLMdata reduction
ELVESdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4HW7

4hw7


Resolution: 2.25→59.226 Å / SU ML: 0.24 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 21
RfactorNum. reflection% reflection
Rfree0.2197 919 5.1 %
Rwork0.1807 --
obs0.1826 18011 99.68 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.25→59.226 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2285 0 29 133 2447
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0092376
X-RAY DIFFRACTIONf_angle_d0.9553218
X-RAY DIFFRACTIONf_dihedral_angle_d16.1751407
X-RAY DIFFRACTIONf_chiral_restr0.055349
X-RAY DIFFRACTIONf_plane_restr0.007409
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.25-2.36860.27231260.2082365X-RAY DIFFRACTION100
2.3686-2.5170.23731340.19582400X-RAY DIFFRACTION100
2.517-2.71140.2461210.18932391X-RAY DIFFRACTION100
2.7114-2.98420.25831380.19362419X-RAY DIFFRACTION100
2.9842-3.4160.2331440.18252407X-RAY DIFFRACTION100
3.416-4.30370.18851440.15842449X-RAY DIFFRACTION100
4.3037-59.24630.20711120.18352661X-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)
10.4590.0946-0.85942.67791.42822.62520.12650.1955-0.07620.14140.0483-0.3508-0.21290.5603-0.1660.3423-0.03160.01660.29560.01920.310914.2708-20.3867-29.0099
22.50690.4852-0.18673.51762.22293.54260.08480.078-0.00260.1638-0.00860.15390.2427-0.23290.00380.2727-0.0067-0.03770.25760.03840.23212.3006-18.9019-27.3577
31.91420.2912-0.54933.0092-0.38711.73710.0316-0.00170.37470.1599-0.0284-0.3263-0.19580.1819-0.03470.2825-0.0251-0.01680.29880.00990.298412.5039-13.5759-22.0886
40.8613-0.5799-0.16490.76370.30080.4155-0.07870.0989-0.12540.00610.02750.11020.0988-0.20510.02320.29840.0049-0.03910.24840.01840.2931-3.4781-21.0059-14.6458
57.555-1.0704-1.41281.12890.69511.85380.0567-0.1082-0.4482-0.0979-0.0916-0.01990.53610.01850.10550.30760.0149-0.03220.18060.02890.23822.8166-28.9992-4.6693
61.2672-1.012-0.12021.71230.03812.28570.08490.06730.1585-0.1464-0.0566-0.2214-0.1950.0884-0.02410.2051-0.02710.00590.22510.00720.23865.5756-12.8017-7.7863
71.2957-0.6682-0.40311.0631-0.16651.1720.0274-0.19040.09810.10220.0042-0.11670.10050.1124-0.02110.2321-0.0126-0.03540.26210.00350.23215.0783-18.42326.1412
81.9999-1.46861.99991.99967.21281.99990.0170.2462-0.012-0.3134-0.0542-0.1470.13730.01930.03021.0165-0.131-0.33720.9153-0.09110.9914-5.2716-39.00910.7189
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 566 through 584 )
2X-RAY DIFFRACTION2chain 'A' and (resid 585 through 610 )
3X-RAY DIFFRACTION3chain 'A' and (resid 611 through 640 )
4X-RAY DIFFRACTION4chain 'A' and (resid 641 through 751 )
5X-RAY DIFFRACTION5chain 'A' and (resid 752 through 772 )
6X-RAY DIFFRACTION6chain 'A' and (resid 773 through 823 )
7X-RAY DIFFRACTION7chain 'A' and (resid 824 through 914 )
8X-RAY DIFFRACTION8chain 'A' and (resid 915 through 915 )

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