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- PDB-6il3: Crystal structure of the FLT3 kinase bound to a small molecule in... -

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Basic information

Entry
Database: PDB / ID: 6il3
TitleCrystal structure of the FLT3 kinase bound to a small molecule inhibitor
ComponentsReceptor-type tyrosine-protein kinase FLT3
KeywordsTRANSFERASE / receptor tyrosine kinase type I inhibitor ATP binding domain DFG-in / SIGNALING PROTEIN
Function / homology
Function and homology information


FLT3 mutants bind TKIs / KW2449-resistant FLT3 mutants / semaxanib-resistant FLT3 mutants / crenolanib-resistant FLT3 mutants / gilteritinib-resistant FLT3 mutants / lestaurtinib-resistant FLT3 mutants / midostaurin-resistant FLT3 mutants / pexidartinib-resistant FLT3 mutants / ponatinib-resistant FLT3 mutants / quizartinib-resistant FLT3 mutants ...FLT3 mutants bind TKIs / KW2449-resistant FLT3 mutants / semaxanib-resistant FLT3 mutants / crenolanib-resistant FLT3 mutants / gilteritinib-resistant FLT3 mutants / lestaurtinib-resistant FLT3 mutants / midostaurin-resistant FLT3 mutants / pexidartinib-resistant FLT3 mutants / ponatinib-resistant FLT3 mutants / quizartinib-resistant FLT3 mutants / sorafenib-resistant FLT3 mutants / sunitinib-resistant FLT3 mutants / tandutinib-resistant FLT3 mutants / linifanib-resistant FLT3 mutants / tamatinib-resistant FLT3 mutants / leukocyte homeostasis / lymphocyte proliferation / pro-B cell differentiation / common myeloid progenitor cell proliferation / dendritic cell differentiation / vascular endothelial growth factor receptor activity / phosphatidylinositol 3-kinase activator activity / STAT5 Activation / nuclear glucocorticoid receptor binding / myeloid progenitor cell differentiation / FLT3 signaling through SRC family kinases / cellular response to glucocorticoid stimulus / cytokine receptor activity / STAT5 activation downstream of FLT3 ITD mutants / growth factor binding / cellular response to cytokine stimulus / hemopoiesis / PI3K Cascade / animal organ regeneration / Signaling by FLT3 ITD and TKD mutants / positive regulation of tyrosine phosphorylation of STAT protein / FLT3 signaling by CBL mutants / cell surface receptor protein tyrosine kinase signaling pathway / : / Negative regulation of FLT3 / FLT3 Signaling / transmembrane receptor protein tyrosine kinase activity / B cell differentiation / positive regulation of MAP kinase activity / receptor protein-tyrosine kinase / cytokine-mediated signaling pathway / peptidyl-tyrosine phosphorylation / Constitutive Signaling by Aberrant PI3K in Cancer / : / PIP3 activates AKT signaling / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / RAF/MAP kinase cascade / regulation of apoptotic process / protein tyrosine kinase activity / positive regulation of MAPK cascade / protein autophosphorylation / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor complex / endosome membrane / endoplasmic reticulum lumen / positive regulation of cell population proliferation / protein-containing complex binding / endoplasmic reticulum / ATP binding / plasma membrane
Similarity search - Function
Tyrosine-protein kinase, receptor class III, conserved site / Receptor tyrosine kinase class III signature. / Immunoglobulin / Immunoglobulin domain / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / Tyrosine-protein kinase, active site / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain ...Tyrosine-protein kinase, receptor class III, conserved site / Receptor tyrosine kinase class III signature. / Immunoglobulin / Immunoglobulin domain / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / 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-A9R / PHOSPHATE ION / Receptor-type tyrosine-protein kinase FLT3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.5 Å
AuthorsThomas, C.J.
CitationJournal: To Be Published
Title: Crystal structure of the FLT3 kinase bound to a small molecule inhibitor
Authors: Thomas, C.J.
History
DepositionOct 16, 2018Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Dec 12, 2018Provider: repository / Type: Initial release
Revision 1.1Mar 27, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Receptor-type tyrosine-protein kinase FLT3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)45,20021
Polymers43,0451
Non-polymers2,15520
Water59433
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3920 Å2
ΔGint-50 kcal/mol
Surface area14840 Å2
Unit cell
Length a, b, c (Å)81.641, 81.641, 147.843
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number96
Space group name H-MP43212

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Components

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Protein , 1 types, 1 molecules A

#1: Protein Receptor-type tyrosine-protein kinase FLT3 / FL cytokine receptor / Fetal liver kinase-2 / FLK-2 / Fms-like tyrosine kinase 3 / FLT-3 / Stem ...FL cytokine receptor / Fetal liver kinase-2 / FLK-2 / Fms-like tyrosine kinase 3 / FLT-3 / Stem cell tyrosine kinase 1 / STK-1


Mass: 43044.816 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FLT3, CD135, FLK2, STK1 / Production host: Baculovirus expression vector pFastBac1-HM
References: UniProt: P36888, receptor protein-tyrosine kinase

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Non-polymers , 6 types, 53 molecules

#2: Chemical ChemComp-A9R / 7-methoxy-6-(1-methyl-1H-pyrazol-4-yl)-3-(pyridin-2-yl)imidazo[1,2-a]pyridine


Mass: 305.334 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H15N5O
#3: Chemical
ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: PO4
#4: Chemical ChemComp-CXS / 3-CYCLOHEXYL-1-PROPYLSULFONIC ACID


Mass: 221.317 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C9H19NO3S / Comment: pH buffer*YM
#5: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 10 / Source method: obtained synthetically / Formula: C3H8O3
#6: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Cl
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 33 / 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: 2.86 Å3/Da / Density % sol: 57.02 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 10.5
Details: 0.2 M Lithium Sulfate, 0.1 M CAPS, pH 10.5, 1.2 M Sodium dihydrogen phosphate, 0.8 M Di-potassium hydrogen phosphate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL18U1 / Wavelength: 0.979 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Dec 31, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 2.5→45.5 Å / Num. obs: 18033 / % possible obs: 100 % / Redundancy: 24.9 % / Rmerge(I) obs: 0.152 / Net I/σ(I): 16.7
Reflection shellResolution: 2.5→2.6 Å / Redundancy: 24.4 %

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Processing

Software
NameVersionClassification
REFMAC5.8.0232refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementResolution: 2.5→45.5 Å / Cor.coef. Fo:Fc: 0.957 / Cor.coef. Fo:Fc free: 0.945 / Cross valid method: THROUGHOUT / ESU R: 0.308 / ESU R Free: 0.222 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.21863 946 5.3 %RANDOM
Rwork0.183 ---
obs0.18491 17029 99.96 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 60.251 Å2
Baniso -1Baniso -2Baniso -3
1-0.49 Å2-0 Å2-0 Å2
2--0.49 Å2-0 Å2
3----0.97 Å2
Refinement stepCycle: 1 / Resolution: 2.5→45.5 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2501 0 134 33 2668
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0150.0132726
X-RAY DIFFRACTIONr_bond_other_d0.0340.0172492
X-RAY DIFFRACTIONr_angle_refined_deg1.8421.6753668
X-RAY DIFFRACTIONr_angle_other_deg2.2671.6095778
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.6225312
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.42322.426136
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.07415451
X-RAY DIFFRACTIONr_dihedral_angle_4_deg12.2121514
X-RAY DIFFRACTIONr_chiral_restr0.1280.2321
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.022973
X-RAY DIFFRACTIONr_gen_planes_other0.0060.02605
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it3.5986.1171248
X-RAY DIFFRACTIONr_mcbond_other3.5646.1151247
X-RAY DIFFRACTIONr_mcangle_it5.5199.1711560
X-RAY DIFFRACTIONr_mcangle_other5.5239.1751561
X-RAY DIFFRACTIONr_scbond_it4.3226.7381478
X-RAY DIFFRACTIONr_scbond_other4.3216.741479
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other6.9419.8562109
X-RAY DIFFRACTIONr_long_range_B_refined9.34167.7272870
X-RAY DIFFRACTIONr_long_range_B_other9.38367.7282867
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.5→2.565 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.325 64 -
Rwork0.277 1229 -
obs--99.92 %

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