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- PDB-4xuf: Crystal structure of the FLT3 kinase domain bound to the inhibito... -

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Basic information

Entry
Database: PDB / ID: 4xuf
TitleCrystal structure of the FLT3 kinase domain bound to the inhibitor quizartinib (AC220)
ComponentsReceptor-type tyrosine-protein kinase FLT3
KeywordsTransferase/transferase inhibitor / FLT3 / receptor tyrosine kinase / AC220 / quizartinib / Transferase-transferase inhibitor 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-P30 / Receptor-type tyrosine-protein kinase FLT3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.2 Å
AuthorsZorn, J.A. / Wang, Q. / Fujimura, E. / Barros, T. / Kuriyan, J.
Funding support United States, 3items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)F32 CA177087-02 United States
Cancer Research Institute United States
Howard Hughes Medical Institute (HHMI) United States
CitationJournal: Plos One / Year: 2015
Title: Crystal Structure of the FLT3 Kinase Domain Bound to the Inhibitor Quizartinib (AC220).
Authors: Zorn, J.A. / Wang, Q. / Fujimura, E. / Barros, T. / Kuriyan, J.
History
DepositionJan 25, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 15, 2015Provider: repository / Type: Initial release
Revision 1.1Apr 29, 2015Group: Database references
Revision 1.2Aug 26, 2015Group: Experimental preparation
Revision 1.3Sep 6, 2017Group: Author supporting evidence / Derived calculations / Category: pdbx_audit_support / pdbx_struct_oper_list
Item: _pdbx_audit_support.funding_organization / _pdbx_struct_oper_list.symmetry_operation
Revision 1.4Nov 20, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.5Sep 27, 2023Group: Data collection / Database references ...Data collection / Database references / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_ncs_dom_lim
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI ..._chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

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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
B: Receptor-type tyrosine-protein kinase FLT3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)69,0854
Polymers67,9642
Non-polymers1,1212
Water362
1
A: Receptor-type tyrosine-protein kinase FLT3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,5432
Polymers33,9821
Non-polymers5611
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Receptor-type tyrosine-protein kinase FLT3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,5432
Polymers33,9821
Non-polymers5611
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)48.726, 75.492, 153.968
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11chain A
21chain B

NCS domain segments:

Component-ID: 1 / Ens-ID: 1 / Beg auth comp-ID: ASP / Beg label comp-ID: ASP

Dom-IDEnd auth comp-IDEnd label comp-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
1LEULEUchain AAA600 - 9471 - 297
2GLNGLNchain BBB600 - 9461 - 296

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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: 33982.051 Da / Num. of mol.: 2 / Fragment: UNP residues 600-710, 762-947 / Mutation: delta(711-761)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FLT3, CD135, FLK2, STK1 / Production host: unidentified baculovirus
References: UniProt: P36888, receptor protein-tyrosine kinase
#2: Chemical ChemComp-P30 / 1-(5-tert-butyl-1,2-oxazol-3-yl)-3-(4-{7-[2-(morpholin-4-yl)ethoxy]imidazo[2,1-b][1,3]benzothiazol-2-yl}phenyl)urea / Quizartinib / PLX3397


Mass: 560.667 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Formula: C29H32N6O4S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 2 / 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: 2.08 Å3/Da / Density % sol: 40.96 %
Crystal growTemperature: 294 K / Method: vapor diffusion, sitting drop / pH: 7.5 / Details: 0.1 M Tris-HCl, pH 7.5, 32% PEG 3350

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Data collection

DiffractionMean temperature: 80 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 8.2.2 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Sep 10, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 3.2→50 Å / Num. obs: 9403 / % possible obs: 94.3 % / Redundancy: 3.5 % / Biso Wilson estimate: 75.04 Å2 / Rmerge(I) obs: 0.209 / Rpim(I) all: 0.131 / Rrim(I) all: 0.248 / Χ2: 1.219 / Net I/av σ(I): 5.545 / Net I/σ(I): 5.3 / Num. measured all: 32682
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allCC1/2Rpim(I) allRrim(I) allΧ2% possible all
3.2-3.312.90.5977440.6980.390.7171.06177.1
3.31-3.453.10.738740.7410.4840.8811.27988.8
3.45-3.63.30.5548920.7660.3630.6661.22392.3
3.6-3.793.50.3489410.8020.220.4141.45995.2
3.79-4.033.60.3859320.9020.2370.4531.06896.5
4.03-4.343.70.249450.9450.1460.2821.34296.7
4.34-4.783.70.2049610.970.1210.2391.23995.8
4.78-5.473.70.19510070.9640.1180.2291.196100
5.47-6.893.60.16710170.9730.1010.1961.20499.9
6.89-503.50.1210900.980.0780.1441.08799.5

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Processing

Software
NameVersionClassification
PHENIX(phenix.refine: dev_1839)refinement
HKL-2000data reduction
PDB_EXTRACT3.15data extraction
HKL-2000data scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 1RJB

1rjb


Resolution: 3.2→46.455 Å / SU ML: 0.53 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 38.52 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.3204 932 10.01 %
Rwork0.2968 8378 -
obs0.2992 9310 91.72 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 127.74 Å2 / Biso mean: 68.1542 Å2 / Biso min: 45.16 Å2
Refinement stepCycle: final / Resolution: 3.2→46.455 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4333 0 80 2 4415
Biso mean--64.99 66.72 -
Num. residues----544
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0044524
X-RAY DIFFRACTIONf_angle_d0.8746114
X-RAY DIFFRACTIONf_chiral_restr0.041650
X-RAY DIFFRACTIONf_plane_restr0.004761
X-RAY DIFFRACTIONf_dihedral_angle_d13.8411668
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDRmsType
11A2286X-RAY DIFFRACTION9.555TORSIONAL
12B2286X-RAY DIFFRACTION9.555TORSIONAL
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 7

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
3.2-3.34030.3884950.367484594066
3.3403-3.54950.40141280.36421137126590
3.5495-3.82340.40461350.34291225136094
3.8234-4.2080.34851350.3031223135895
4.208-4.81630.31391400.28791256139696
4.8163-6.06590.26251460.300613051451100
6.0659-46.46020.26981530.24691387154099

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