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- PDB-6jqr: Crystal structure of FLT3 in complex with gilteritinib -

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Basic information

Entry
Database: PDB / ID: 6jqr
TitleCrystal structure of FLT3 in complex with gilteritinib
ComponentsReceptor-type tyrosine-protein kinase FLT3,Receptor-type tyrosine-protein kinase FLT3
KeywordsTRANSFERASE / protein kinase / ONCOPROTEIN
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 / Negative regulation of FLT3 / response to organonitrogen compound / FLT3 Signaling / transmembrane receptor protein tyrosine kinase activity / B cell differentiation / cell surface receptor protein tyrosine kinase signaling pathway / 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-C6F / Receptor-type tyrosine-protein kinase FLT3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.2 Å
AuthorsAmano, Y.
CitationJournal: Oncotarget / Year: 2019
Title: Effect of Fms-like tyrosine kinase 3 (FLT3) ligand (FL) on antitumor activity of gilteritinib, a FLT3 inhibitor, in mice xenografted with FL-overexpressing cells.
Authors: Kawase, T. / Nakazawa, T. / Eguchi, T. / Tsuzuki, H. / Ueno, Y. / Amano, Y. / Suzuki, T. / Mori, M. / Yoshida, T.
History
DepositionApr 1, 2019Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Nov 20, 2019Provider: 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,Receptor-type tyrosine-protein kinase FLT3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,3389
Polymers37,9991
Non-polymers1,3388
Water1,74797
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area180 Å2
ΔGint-14 kcal/mol
Surface area15130 Å2
MethodPISA
Unit cell
Length a, b, c (Å)82.367, 82.367, 146.469
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-1008-

GOL

21A-1192-

HOH

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Components

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Protein , 1 types, 1 molecules A

#1: Protein Receptor-type tyrosine-protein kinase FLT3,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: 37999.242 Da / Num. of mol.: 1 / Fragment: KINASE DOMAIN / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human)
References: UniProt: P36888, receptor protein-tyrosine kinase

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Non-polymers , 5 types, 105 molecules

#2: Chemical ChemComp-C6F / 6-ethyl-3-[[3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]amino]-5-(oxan-4-ylamino)pyrazine-2-carboxamide / gilteritinib / Gilteritinib


Mass: 552.711 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H44N8O3 / Comment: anticancer, inhibitor*YM
#3: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C3H8O3
#5: Chemical ChemComp-CXS / 3-CYCLOHEXYL-1-PROPYLSULFONIC ACID / CAPS (buffer)


Mass: 221.317 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C9H19NO3S / Comment: pH buffer*YM
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 97 / 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: 3.35 Å3/Da / Density % sol: 63.26 %
Crystal growTemperature: 293 K / Method: vapor diffusion / Details: buffer, salt, precipitant

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.9999 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: May 17, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9999 Å / Relative weight: 1
ReflectionResolution: 2.2→71.79 Å / Num. obs: 24524 / % possible obs: 93.1 % / Observed criterion σ(I): 0 / Redundancy: 15.7 % / Rmerge(I) obs: 0.04 / Net I/σ(I): 49.61
Reflection shellResolution: 2.2→2.45 Å / Redundancy: 16.2 % / Rmerge(I) obs: 0.441 / % possible all: 81.8

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Processing

Software
NameVersionClassification
REFMAC5.8.0155refinement
XDSdata reduction
XSCALEdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.2→71.79 Å / Cor.coef. Fo:Fc: 0.956 / Cor.coef. Fo:Fc free: 0.939 / SU B: 8.171 / SU ML: 0.104 / Cross valid method: THROUGHOUT / ESU R: 0.181 / ESU R Free: 0.162 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.213 1319 5.4 %RANDOM
Rwork0.179 ---
obs0.181 23205 93.1 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 54.61 Å2
Baniso -1Baniso -2Baniso -3
1-0.06 Å20 Å20 Å2
2--0.06 Å20 Å2
3----0.11 Å2
Refinement stepCycle: LAST / Resolution: 2.2→71.79 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2361 0 87 97 2545
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.022500
X-RAY DIFFRACTIONr_bond_other_d0.0030.022327
X-RAY DIFFRACTIONr_angle_refined_deg1.5871.993380
X-RAY DIFFRACTIONr_angle_other_deg1.22735328
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.8115296
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.31324.019107
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.41815393
X-RAY DIFFRACTIONr_dihedral_angle_4_deg11.7191510
X-RAY DIFFRACTIONr_chiral_restr0.0910.2368
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.022762
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02582
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_it3.5554.2731199
X-RAY DIFFRACTIONr_mcbond_other3.5574.2691198
X-RAY DIFFRACTIONr_mcangle_it4.7627.1571490
X-RAY DIFFRACTIONr_mcangle_other4.767.1631491
X-RAY DIFFRACTIONr_scbond_it5.0985.0721301
X-RAY DIFFRACTIONr_scbond_other5.0945.0721301
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other7.2988.2731891
X-RAY DIFFRACTIONr_long_range_B_refined8.15738.2142671
X-RAY DIFFRACTIONr_long_range_B_other8.13637.9392657
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.2→2.26 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.336 58 -
Rwork0.304 933 -
obs--52.52 %
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)
16.3948-2.33766.24491.3606-1.68377.2306-0.2443-0.53850.14710.37210.1367-0.06520.0515-0.41760.10760.3115-0.037-0.05390.1287-0.01630.1134-23.73215.61-22.426
26.6609-1.73092.52225.7716-0.00852.77970.0584-0.3384-0.35480.05840.06230.80010.3215-0.3931-0.12070.2341-0.0785-0.06790.07090.04120.1401-33.6213.46-32.211
31.6749-0.18631.29863.2079-0.92854.60580.04480.1413-0.0538-0.2491-0.0208-0.09810.11120.2437-0.0240.0702-0.011-0.00650.0221-0.00060.0085-12.535-4.573-19.169
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A571 - 603
2X-RAY DIFFRACTION2A604 - 693
3X-RAY DIFFRACTION3A694 - 951

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