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- PDB-5x02: Crystal structure of the FLT3 kinase domain bound to the inhibito... -

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Basic information

Entry
Database: PDB / ID: 5x02
TitleCrystal structure of the FLT3 kinase domain bound to the inhibitor FF-10101
ComponentsReceptor-type tyrosine-protein kinase FLT3
KeywordsTRANSFERASE/TRANSFERASE INIHIBITOR / tyrosine kinase / transferase / irreversible inhibitor complex / kinase catalytic domain / TRANSFERASE-TRANSFERASE INIHIBITOR complex
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 / common myeloid progenitor cell proliferation / pro-B cell differentiation / lymphocyte proliferation / vascular endothelial growth factor receptor activity / dendritic cell differentiation / nuclear glucocorticoid receptor binding / STAT5 Activation / phosphatidylinositol 3-kinase activator activity / FLT3 signaling through SRC family kinases / myeloid progenitor cell differentiation / cytokine receptor activity / positive regulation of tyrosine phosphorylation of STAT protein / cellular response to glucocorticoid stimulus / growth factor binding / STAT5 activation downstream of FLT3 ITD mutants / cellular response to cytokine stimulus / positive regulation of MAP kinase activity / hemopoiesis / PI3K Cascade / Signaling by FLT3 ITD and TKD mutants / FLT3 signaling by CBL mutants / FLT3 Signaling / transmembrane receptor protein tyrosine kinase activity / liver regeneration / Negative regulation of FLT3 / cell surface receptor protein tyrosine kinase signaling pathway / peptidyl-tyrosine phosphorylation / B cell differentiation / receptor protein-tyrosine kinase / cytokine-mediated signaling pathway / Constitutive Signaling by Aberrant PI3K in Cancer / cell migration / PIP3 activates AKT signaling / protein autophosphorylation / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / RAF/MAP kinase cascade / protein tyrosine kinase activity / regulation of apoptotic process / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor complex / positive regulation of MAPK cascade / 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 / 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 / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); 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-F6M / Receptor-type tyrosine-protein kinase FLT3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.401 Å
AuthorsFujikawa, N. / Hirano, D. / Takasaki, M. / Terada, D. / Hagiwara, S. / Park, S.-Y. / Sugiyama, K.
CitationJournal: Blood / Year: 2018
Title: A novel irreversible FLT3 inhibitor, FF-10101, shows excellent efficacy against AML cells withFLT3mutations.
Authors: Yamaura, T. / Nakatani, T. / Uda, K. / Ogura, H. / Shin, W. / Kurokawa, N. / Saito, K. / Fujikawa, N. / Date, T. / Takasaki, M. / Terada, D. / Hirai, A. / Akashi, A. / Chen, F. / Adachi, Y. ...Authors: Yamaura, T. / Nakatani, T. / Uda, K. / Ogura, H. / Shin, W. / Kurokawa, N. / Saito, K. / Fujikawa, N. / Date, T. / Takasaki, M. / Terada, D. / Hirai, A. / Akashi, A. / Chen, F. / Adachi, Y. / Ishikawa, Y. / Hayakawa, F. / Hagiwara, S. / Naoe, T. / Kiyoi, H.
History
DepositionJan 19, 2017Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jan 24, 2018Provider: repository / Type: Initial release
Revision 1.1Feb 6, 2019Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Nov 22, 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
Revision 1.3Nov 20, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)40,8295
Polymers40,0111
Non-polymers8194
Water21612
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area370 Å2
ΔGint-25 kcal/mol
Surface area14350 Å2
MethodPISA
Unit cell
Length a, b, c (Å)81.993, 81.993, 143.558
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 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: 40010.543 Da / Num. of mol.: 1 / Fragment: UNP residues 564-710,762-958
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FLT3, CD135, FLK2, STK1 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P36888, receptor protein-tyrosine kinase
#2: Chemical ChemComp-F6M / N-[(2S)-1-[5-[2-[(4-cyanophenyl)amino]-4-(propylamino)pyrimidin-5-yl]pent-4-ynylamino]-1-oxidanylidene-propan-2-yl]-4-(dimethylamino)-N-methyl-but-2-enamide


Mass: 530.664 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H38N8O2
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 12 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

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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: 3.02 Å3/Da / Density % sol: 59.21 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 6.7
Details: 2.2-2.4M Na/K Phosphate, 0.1M CAPS (pH6.7), 0.2M Litium Sulfate

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Photon Factory / Beamline: BL-17A / Wavelength: 0.98 Å
DetectorType: ADSC QUANTUM 270 / Detector: CCD / Date: Feb 19, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 2.4→50 Å / Num. obs: 19769 / % possible obs: 99.5 % / Redundancy: 14.2 % / Net I/σ(I): 57.6

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Processing

Software
NameVersionClassification
PHENIXrefinement
PDB_EXTRACT3.22data extraction
HKL-2000data reduction
HKL-2000data scaling
MOLREPphasing
REFMACrefinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1RJB

1rjb


Resolution: 2.401→36.906 Å / SU ML: 0.32 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 28.96
RfactorNum. reflection% reflectionSelection details
Rfree0.2766 1007 5.11 %RANDOM
Rwork0.234 ---
obs0.236 19705 99.43 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 141.59 Å2 / Biso mean: 74.3646 Å2 / Biso min: 42.61 Å2
Refinement stepCycle: final / Resolution: 2.401→36.906 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2448 0 54 12 2514
Biso mean--88.36 61.81 -
Num. residues----305

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