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- PDB-4rt7: Crystal Structure of FLT3 with a small molecule inhibitor -

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Basic information

Entry
Database: PDB / ID: 4rt7
TitleCrystal Structure of FLT3 with a small molecule inhibitor
ComponentsReceptor-type tyrosine-protein kinase FLT3
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Kinase / TRANSFERASE / TRANSFERASE INHIBITOR / COMPLEX / 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 / lymphocyte proliferation / common myeloid progenitor cell proliferation / pro-B cell differentiation / nuclear glucocorticoid receptor binding / dendritic cell differentiation / phosphatidylinositol 3-kinase activator activity / STAT5 Activation / myeloid progenitor cell differentiation / FLT3 signaling through SRC family kinases / cytokine receptor activity / cellular response to glucocorticoid stimulus / positive regulation of tyrosine phosphorylation of STAT protein / STAT5 activation downstream of FLT3 ITD mutants / growth factor binding / cellular response to cytokine stimulus / hemopoiesis / PI3K Cascade / Signaling by FLT3 ITD and TKD mutants / transmembrane receptor protein tyrosine kinase activity / FLT3 Signaling / FLT3 signaling by CBL mutants / Negative regulation of FLT3 / positive regulation of MAP kinase activity / B cell differentiation / cell surface receptor protein tyrosine kinase signaling pathway / liver regeneration / placental growth factor receptor activity / insulin receptor activity / vascular endothelial growth factor receptor activity / hepatocyte growth factor receptor activity / macrophage colony-stimulating factor receptor activity / platelet-derived growth factor alpha-receptor activity / platelet-derived growth factor beta-receptor activity / stem cell factor receptor activity / boss receptor activity / protein tyrosine kinase collagen receptor activity / brain-derived neurotrophic factor receptor activity / transmembrane-ephrin receptor activity / GPI-linked ephrin receptor activity / epidermal growth factor receptor activity / fibroblast growth factor receptor activity / cytokine-mediated signaling pathway / insulin-like growth factor receptor activity / receptor protein-tyrosine kinase / peptidyl-tyrosine phosphorylation / Constitutive Signaling by Aberrant PI3K in Cancer / cell migration / PIP3 activates AKT signaling / RAF/MAP kinase cascade / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / protein autophosphorylation / 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 / Ig-like domain profile. / Immunoglobulin-like domain / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Immunoglobulin-like domain superfamily / Transferase(Phosphotransferase); domain 1 / 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: 3.1 Å
AuthorsZhang, Y. / Zhang, C.
CitationJournal: Cancer Discov / Year: 2015
Title: Characterizing and Overriding the Structural Mechanism of the Quizartinib-Resistant FLT3 "Gatekeeper" F691L Mutation with PLX3397.
Authors: Smith, C.C. / Zhang, C. / Lin, K.C. / Lasater, E.A. / Zhang, Y. / Massi, E. / Damon, L.E. / Pendleton, M. / Bashir, A. / Sebra, R. / Perl, A. / Kasarskis, A. / Shellooe, R. / Tsang, G. / ...Authors: Smith, C.C. / Zhang, C. / Lin, K.C. / Lasater, E.A. / Zhang, Y. / Massi, E. / Damon, L.E. / Pendleton, M. / Bashir, A. / Sebra, R. / Perl, A. / Kasarskis, A. / Shellooe, R. / Tsang, G. / Carias, H. / Powell, B. / Burton, E.A. / Matusow, B. / Zhang, J. / Spevak, W. / Ibrahim, P.N. / Le, M.H. / Hsu, H.H. / Habets, G. / West, B.L. / Bollag, G. / Shah, N.P.
History
DepositionNov 13, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 22, 2015Provider: repository / Type: Initial release
Revision 1.1Jun 17, 2015Group: Database references
Revision 1.2Nov 6, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / pdbx_entry_details / pdbx_modification_feature / struct_ref_seq_dif / struct_site
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI ..._chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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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)48,7612
Polymers48,2001
Non-polymers5611
Water181
1
A: Receptor-type tyrosine-protein kinase FLT3
hetero molecules

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


Theoretical massNumber of molelcules
Total (without water)97,5224
Polymers96,4012
Non-polymers1,1212
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation6_554-x,-x+y,-z-1/31
Buried area1460 Å2
ΔGint-8 kcal/mol
Surface area24560 Å2
MethodPISA
Unit cell
Length a, b, c (Å)78.880, 78.880, 138.360
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number154
Space group name H-MP3221

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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: 48200.316 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: Spodoptera frugiperda (fall armyworm)
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.: 1 / Source method: obtained synthetically / Formula: C29H32N6O4S / Comment: medication, anticancer, inhibitor*YM
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1 / 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: 2.58 Å3/Da / Density % sol: 52.29 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 5.5
Details: 100mM Na-Citrate, pH5.5 and 20% PEG3000, VAPOR DIFFUSION, SITTING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 8.3.1 / Wavelength: 1.1159 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Mar 25, 2014
RadiationMonochromator: DOUBLE FLAT CRYSTAL, SI(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.1159 Å / Relative weight: 1
ReflectionResolution: 3.1→61.253 Å / Num. all: 9504 / Num. obs: 8651 / % possible obs: 91.02 % / Observed criterion σ(F): -3 / Observed criterion σ(I): -3

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Processing

Software
NameVersionClassification
Blu-Icedata collection
MOLREPphasing
PHENIX(phenix.refine: 1.7.3_928)refinement
MOSFLMdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 3.1→61.253 Å / SU ML: 0.42 / σ(F): 0.07 / Phase error: 24.86 / Stereochemistry target values: MLHL
RfactorNum. reflection% reflectionSelection details
Rfree0.2677 868 10.03 %RANDOM
Rwork0.2185 ---
obs0.2236 8651 91.02 %-
all-9504 --
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 26.74 Å2 / ksol: 0.327 e/Å3
Displacement parameters
Baniso -1Baniso -2Baniso -3
1-5.5825 Å2-0 Å2-0 Å2
2--5.5825 Å2-0 Å2
3----11.165 Å2
Refinement stepCycle: LAST / Resolution: 3.1→61.253 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2180 0 40 1 2221
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0052280
X-RAY DIFFRACTIONf_angle_d0.8983082
X-RAY DIFFRACTIONf_dihedral_angle_d14.769821
X-RAY DIFFRACTIONf_chiral_restr0.064328
X-RAY DIFFRACTIONf_plane_restr0.004384
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.1003-3.29450.34261180.28921149X-RAY DIFFRACTION81
3.2945-3.54880.30461420.25721206X-RAY DIFFRACTION87
3.5488-3.90590.26431410.22861285X-RAY DIFFRACTION91
3.9059-4.4710.22541490.19441304X-RAY DIFFRACTION93
4.471-5.63240.23571520.18821375X-RAY DIFFRACTION95
5.6324-61.2650.291660.21351464X-RAY DIFFRACTION97
Refinement TLS params.Method: refined / Origin x: -31.283 Å / Origin y: 11.5004 Å / Origin z: -14.5792 Å
111213212223313233
T0.3954 Å2-0.041 Å2-0.0568 Å2-0.2457 Å20.0147 Å2--0.3161 Å2
L3.7078 °20.6516 °2-2.1659 °2-0.6017 °2-0.2562 °2--3.6208 °2
S0.0955 Å °0.0378 Å °-0.218 Å °0.0905 Å °-0.0915 Å °0.0215 Å °0.3276 Å °-0.1512 Å °-0.0322 Å °
Refinement TLS groupSelection details: chain A

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