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- PDB-7qdp: Crystal structure of FLT3 T343I in complex with the canonical lig... -

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Basic information

Entry
Database: PDB / ID: 7qdp
TitleCrystal structure of FLT3 T343I in complex with the canonical ligand FL
Components
  • Fms-related tyrosine kinase 3 ligand
  • Receptor-type tyrosine-protein kinase FLT3
KeywordsSIGNALING PROTEIN / Activation complex / Complex / Receptor Tyrosine Kinase / RTK-III
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 / embryonic hemopoiesis / 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 / cytokine activity / cell surface receptor protein tyrosine kinase signaling pathway / positive regulation of MAP kinase activity / receptor protein-tyrosine kinase / receptor tyrosine kinase binding / 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 / signaling receptor binding / positive regulation of cell population proliferation / protein-containing complex binding / cell surface / endoplasmic reticulum / signal transduction / extracellular space / extracellular region / ATP binding / membrane / plasma membrane / cytosol
Similarity search - Function
Flt3 ligand / flt3 ligand / Tyrosine-protein kinase, receptor class III, conserved site / Receptor tyrosine kinase class III signature. / Four-helical cytokine-like, core / Immunoglobulin / Immunoglobulin domain / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. ...Flt3 ligand / flt3 ligand / Tyrosine-protein kinase, receptor class III, conserved site / Receptor tyrosine kinase class III signature. / Four-helical cytokine-like, core / 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 / 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
Similarity search - Domain/homology
Receptor-type tyrosine-protein kinase FLT3 / Fms-related tyrosine kinase 3 ligand
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.691 Å
AuthorsPannecoucke, E. / Savvides, S.N.
Funding support Belgium, 1items
OrganizationGrant numberCountry
Research Foundation - Flanders (FWO) Belgium
CitationJournal: To Be Published
Title: Crystal structure of FLT3 T343I in complex with the canonical ligand FL
Authors: Pannecoucke, E. / Savvides, S.N.
History
DepositionNov 27, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 14, 2022Provider: repository / Type: Initial release
Revision 1.1Jan 31, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

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MolmilJmol/JSmol

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Assembly

Deposited unit
A: Fms-related tyrosine kinase 3 ligand
B: Fms-related tyrosine kinase 3 ligand
C: Fms-related tyrosine kinase 3 ligand
D: Fms-related tyrosine kinase 3 ligand
E: Receptor-type tyrosine-protein kinase FLT3
F: Receptor-type tyrosine-protein kinase FLT3
G: Receptor-type tyrosine-protein kinase FLT3
H: Receptor-type tyrosine-protein kinase FLT3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)334,22514
Polymers332,3298
Non-polymers1,8966
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: light scattering
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area9650 Å2
ΔGint-18 kcal/mol
Surface area110410 Å2
Unit cell
Length a, b, c (Å)102.428, 113.377, 123.225
Angle α, β, γ (deg.)105.37, 109.47, 108.22
Int Tables number1
Space group name H-MP1

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Components

#1: Protein
Fms-related tyrosine kinase 3 ligand / Flt3 ligand / Flt3L / SL cytokine


Mass: 17762.312 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FLT3LG / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P49771
#2: 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: 65319.879 Da / Num. of mol.: 4 / Mutation: T343I
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FLT3, CD135, FLK2, STK1 / Plasmid: pcDNA4/TO / Production host: Homo sapiens (human) / Strain (production host): Human embryonic kidney 293 / Variant (production host): MGAT-/- TR+
References: UniProt: P36888, receptor protein-tyrosine kinase
#3: Polysaccharide beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta- ...beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 586.542 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/2,3,2/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5]/1-1-2/a4-b1_b4-c1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{}}}LINUCSPDB-CARE
#4: Polysaccharide 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}LINUCSPDB-CARE
#5: Sugar
ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE / N-Acetylglucosamine


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0
Has ligand of interestN

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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: 3.51 Å3/Da / Density % sol: 64.99 %
Crystal growTemperature: 287 K / Method: vapor diffusion, sitting drop / pH: 6.6 / Details: 15 % PEG 3350 25% ethylene glycol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: PETRA III, DESY / Beamline: P11 / Wavelength: 0.98 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Sep 4, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 3.691→48.58 Å / Num. obs: 45955 / % possible obs: 94.1 % / Redundancy: 1.84 % / Biso Wilson estimate: 144.26 Å2 / CC1/2: 0.996 / Net I/σ(I): 4.71
Reflection shellResolution: 3.691→3.822 Å / Mean I/σ(I) obs: 0.46 / Num. unique obs: 7248 / CC1/2: 0.17

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Processing

Software
NameVersionClassification
BUSTER2.10.3refinement
MxCuBEdata collection
XDSdata reduction
XDSdata scaling
Cootmodel building
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3QS7

3qs7


Resolution: 3.691→48.58 Å / Cor.coef. Fo:Fc: 0.903 / Cor.coef. Fo:Fc free: 0.895 / Cross valid method: THROUGHOUT / SU Rfree Blow DPI: 0.535
RfactorNum. reflection% reflectionSelection details
Rfree0.2765 2298 -RANDOM
Rwork0.2571 ---
obs0.258 45945 94.5 %-
Displacement parametersBiso mean: 237.58 Å2
Baniso -1Baniso -2Baniso -3
1--2.8593 Å215.3228 Å224.2865 Å2
2---19.4159 Å215.3597 Å2
3---22.2752 Å2
Refine analyzeLuzzati coordinate error obs: 0.86 Å
Refinement stepCycle: LAST / Resolution: 3.691→48.58 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms13362 0 123 0 13485
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.00713825HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.9919007HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d4019SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes2393HARMONIC5
X-RAY DIFFRACTIONt_it13825HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion2068SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies3HARMONIC1
X-RAY DIFFRACTIONt_ideal_dist_contact8497SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion2.92
X-RAY DIFFRACTIONt_other_torsion20.93
LS refinement shellResolution: 3.691→3.72 Å
RfactorNum. reflection% reflection
Rfree0.2189 46 -
Rwork0.2333 --
obs--69.95 %
Refinement TLS params.

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)
17.1247-2.12892.47046.72961.04717.89620.3873-0.3255-0.1556-0.3255-0.1848-0.0124-0.1556-0.0124-0.2024-0.3002-0.21110.136-0.0168-0.0979-0.35968.6283-5.448742.4022
23.65491.4214-1.23116.45050.06955.7528-0.1278-0.0427-0.3452-0.04270.1791-0.1974-0.3452-0.1974-0.05130.002-0.09150.0558-0.0329-0.0993-0.4718-10.574124.262158.2821
310.88411.2088-0.62698.11250.87595.3213-0.00020.7477-0.55210.74770.01850.0121-0.55210.0121-0.0183-0.1472-0.05980.14660.0955-0.0105-0.2368-32.12864.777562.0021
45.90130.22030.52737.4631-0.116412.83490.0749-0.0291-0.5778-0.0291-0.41030.3075-0.57780.30750.33530.0567-0.01360.0472-0.31580.0345-0.3581-14.68297.88129.2389
53.7140.27950.80852.1312-3.220111.45190.141.08-0.47441.08-0.4242-0.1272-0.4744-0.12720.28420.1123-0.21470.01310.09420.03230.005235.0617-16.735289.8543
614.59-2.36973.76753.2978-0.61543.7692-0.07380.6270.44970.627-0.0250.38750.44970.38750.09880.0754-0.13210.16090.1468-0.0982-0.293220.839920.585198.5097
72.7871.50270.9525.682.84323.53750.1281-0.25570.8976-0.2557-0.0617-0.18480.8976-0.1848-0.06640.1233-0.09890.11490.220.24-0.0484-59.376-42.521246.9908
811.4664.2518-4.11197.5184-0.572810.3381-0.22250.01450.77840.01450.106-0.56510.7784-0.56510.1164-0.24240.08080.14910.0356-0.1385-0.448-39.2894-27.0228.0357
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A-10 - 134
2X-RAY DIFFRACTION2{ B|* }B0 - 133
3X-RAY DIFFRACTION3{ C|* }C2 - 134
4X-RAY DIFFRACTION4{ D|* }D1 - 134
5X-RAY DIFFRACTION5{ E|* }E164 - 531
6X-RAY DIFFRACTION5{ E|* }E535
7X-RAY DIFFRACTION6{ F|* }F74 - 526
8X-RAY DIFFRACTION6{ F|* }F535 - 539
9X-RAY DIFFRACTION7{ G|* }G164 - 531
10X-RAY DIFFRACTION8{ H|* }H156 - 502
11X-RAY DIFFRACTION8{ H|* }H535 - 537

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