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- PDB-7zv9: Crystal structure of FLT3 in complex with a monomeric FLT3 Ligand... -

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Basic information

Entry
Database: PDB / ID: 7zv9
TitleCrystal structure of FLT3 in complex with a monomeric FLT3 Ligand variant
Components
  • Fms-related tyrosine kinase 3 ligand
  • Receptor-type tyrosine-protein kinase FLT3
KeywordsSIGNALING PROTEIN / Inactive 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: 4.507 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 in complex with a monomeric FLT3 Ligand variant
Authors: Pannecoucke, E. / Savvides, S.N.
History
DepositionMay 14, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 31, 2023Provider: repository / Type: Initial release
Revision 1.1Feb 7, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Fms-related tyrosine kinase 3 ligand
B: Receptor-type tyrosine-protein kinase FLT3
C: Fms-related tyrosine kinase 3 ligand
D: Receptor-type tyrosine-protein kinase FLT3
E: Fms-related tyrosine kinase 3 ligand
F: Receptor-type tyrosine-protein kinase FLT3
G: Fms-related tyrosine kinase 3 ligand
H: Receptor-type tyrosine-protein kinase FLT3
I: Fms-related tyrosine kinase 3 ligand
J: Receptor-type tyrosine-protein kinase FLT3
K: Fms-related tyrosine kinase 3 ligand
L: Receptor-type tyrosine-protein kinase FLT3
M: Fms-related tyrosine kinase 3 ligand
N: Receptor-type tyrosine-protein kinase FLT3
O: Fms-related tyrosine kinase 3 ligand
P: Receptor-type tyrosine-protein kinase FLT3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)668,00826
Polymers664,57716
Non-polymers3,43110
Water0
1
A: Fms-related tyrosine kinase 3 ligand
B: Receptor-type tyrosine-protein kinase FLT3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)83,5144
Polymers83,0722
Non-polymers4422
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
C: Fms-related tyrosine kinase 3 ligand
D: Receptor-type tyrosine-protein kinase FLT3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)83,4963
Polymers83,0722
Non-polymers4241
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
E: Fms-related tyrosine kinase 3 ligand
F: Receptor-type tyrosine-protein kinase FLT3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)83,4963
Polymers83,0722
Non-polymers4241
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
G: Fms-related tyrosine kinase 3 ligand
H: Receptor-type tyrosine-protein kinase FLT3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)83,2933
Polymers83,0722
Non-polymers2211
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
5
I: Fms-related tyrosine kinase 3 ligand
J: Receptor-type tyrosine-protein kinase FLT3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)83,4963
Polymers83,0722
Non-polymers4241
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
6
K: Fms-related tyrosine kinase 3 ligand
L: Receptor-type tyrosine-protein kinase FLT3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)83,4963
Polymers83,0722
Non-polymers4241
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
7
M: Fms-related tyrosine kinase 3 ligand
N: Receptor-type tyrosine-protein kinase FLT3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)83,4963
Polymers83,0722
Non-polymers4241
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
8
O: Fms-related tyrosine kinase 3 ligand
P: Receptor-type tyrosine-protein kinase FLT3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)83,7184
Polymers83,0722
Non-polymers6462
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)139.208, 139.215, 143.689
Angle α, β, γ (deg.)90.02, 90.03, 89.99
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: 17764.242 Da / Num. of mol.: 8 / Mutation: L27D
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: 65307.824 Da / Num. of mol.: 8
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
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.: 6
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
#4: 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: 4.19 Å3/Da / Density % sol: 70.67 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8.3
Details: 0.9 M ammonium sulfate 10% PEG 8000 MES buffer pH 8.3

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06DA / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 2M-F / Detector: PIXEL / Date: Oct 25, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 4.3→50 Å / Num. obs: 68007 / % possible obs: 92.3 % / Redundancy: 1.68 % / CC1/2: 0.998 / Net I/σ(I): 7.64
Reflection shellResolution: 4.3→4.6 Å / Redundancy: 1.66 % / Mean I/σ(I) obs: 0.44 / Num. unique obs: 1187 / CC1/2: 0.222 / % possible all: 93

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Processing

Software
NameVersionClassification
BUSTER2.10.3refinement
PHENIX1.20-4459refinement
XDSdata scaling
PHASERphasing
Cootmodel building
PDB-REDOrefinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3QS7

3qs7


Resolution: 4.507→47.9 Å / Cor.coef. Fo:Fc: 0.841 / Cor.coef. Fo:Fc free: 0.792 / Cross valid method: THROUGHOUT / SU Rfree Blow DPI: 1.136
RfactorNum. reflection% reflectionSelection details
Rfree0.2913 2027 -RANDOM
Rwork0.2777 ---
obs0.2784 42090 66.2 %-
Displacement parametersBiso mean: 200.99 Å2
Baniso -1Baniso -2Baniso -3
1--1.9395 Å25.463 Å2-10.0354 Å2
2---9.1462 Å20.657 Å2
3---11.0857 Å2
Refine analyzeLuzzati coordinate error obs: 1.01 Å
Refinement stepCycle: LAST / Resolution: 4.507→47.9 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms26467 0 224 0 26691
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.00527132HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.8337588HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d6770SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes4917HARMONIC5
X-RAY DIFFRACTIONt_it26892HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion4555SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact14098SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion5.61
X-RAY DIFFRACTIONt_other_torsion21.37
LS refinement shellResolution: 4.51→4.64 Å
RfactorNum. reflection% reflection
Rfree0.3118 32 -
Rwork0.2067 --
obs0.2114 842 15.7 %
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)
18.50644.9421-2.02174.22990.55014.8870.20920.0687-0.07620.0687-0.385-0.9412-0.0762-0.94120.17580.2210.2172-0.3040.60780.05620.3467-117.3807-54.351971.4293
216.62742.42394.203112.2065-0.361216.63490.1330.7782-1.08820.77820.1327-1.0885-1.0882-1.0885-0.2657-0.00960.1574-0.2037-0.36160.01580.6077-68.7438-36.631232.1762
316.6348-0.5547-4.050112.72862.053816.6280.0623-0.59330.316-0.5933-0.3856-1.04540.316-1.04540.32330.0329-0.0131-0.0003-0.2927-0.16720.6078-68.674-97.67873.4088
45.6467-4.0566-1.07993.4444-0.80914.88390.0122-0.2719-0.3521-0.2719-0.31621.058-0.35211.0580.30410.15-0.1371-0.27840.60790.14710.5519-14.9145-53.931336.0178
57.94284.79312.93654.0774-0.85596.4382-0.14220.15460.37340.1546-0.21311.0880.37341.0880.3553-0.00010.13370.12270.60770.27180.5764-15.2288-80.3029-0.7681
614.11361.69592.973215.37-5.820816.63050.1073-0.79311.0883-0.7931-0.3070.71181.08830.71180.1998-0.29880.14540.0183-0.11160.20180.6081-35.5807-69.9578-32.762
73.8152-3.57720.17347.33431.85334.5828-0.17250.4674-1.08850.4674-0.06150.1857-1.08850.18570.2340.6082-0.1962-0.30390.27910.21980.3702-53.0697-16.0663-36.6832
811.2486-0.5217-1.303916.62765.820816.6330.585-1.0424-1.0885-1.0424-0.2057-0.9393-1.0885-0.9393-0.3793-0.19410.1591-0.30430.0299-00.6076-96.6902-64.608938.9437
92.0612-3.6658-0.11736.1011-1.34875.43750.18451.06610.83721.0661-0.52180.13210.83720.13210.33740.6078-0.26380.01830.089-0.1190.4531-78.9028-118.396135.1541
1011.97370.3673-2.130216.6342-5.820316.62530.36621.0886-1.0881.0886-0.64270.8487-1.0880.84870.2765-0.410.07-0.15820.16030.16270.5966-35.625-64.409968.118
113.54133.3951-0.08712.04692.93133.3196-0.11450.25331.08860.25330.20810.34791.08860.3479-0.09360.6080.2474-0.03890.21260.18110.4449-53.2123-118.64171.9764
1216.635-5.8202-5.822511.54470.559616.6253-0.48451.08851.08871.08850.53770.88051.08870.8805-0.0532-0.0403-0.0495-0.0612-0.21760.05160.6079-63.5959-97.6548-39.7585
1310.4567-4.65763.60414.99380.02615.4482-0.0084-0.00270.1661-0.0027-0.229-1.08880.1661-1.08880.23740.0425-0.22330.1690.608-0.06870.2995-117.5024-80.0149-35.8578
1415.5516-2.806-2.670415.93455.819616.6317-0.00261.05221.08891.05220.3492-0.72411.0889-0.7241-0.3466-0.1491-0.06220.0888-0.1105-0.00030.593-96.4097-70.1515-3.4446
155.09675.241-1.31410.1175-4.93387.7239-0.1737-0.4083-1.0085-0.4083-0.14950.1138-1.00850.11380.32320.60820.091-0.25520.0634-0.14650.0239-79.1803-16.2034-0.3407
1615.72974.53145.821713.39190.258316.6369-0.4959-0.5413-0.9381-0.54130.59171.0894-0.93811.0894-0.0958-0.19850.0628-0.1917-0.31590.12760.6052-63.3061-36.86474.9481
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{ N|* }
2X-RAY DIFFRACTION2{ A|* }
3X-RAY DIFFRACTION3{ O|* }
4X-RAY DIFFRACTION4{ B|* }
5X-RAY DIFFRACTION5{ P|* }
6X-RAY DIFFRACTION6{ C|* }
7X-RAY DIFFRACTION7{ D|* }
8X-RAY DIFFRACTION8{ E|* }
9X-RAY DIFFRACTION9{ F|* }
10X-RAY DIFFRACTION10{ G|* }
11X-RAY DIFFRACTION11{ H|* }
12X-RAY DIFFRACTION12{ I|* }
13X-RAY DIFFRACTION13{ J|* }
14X-RAY DIFFRACTION14{ K|* }
15X-RAY DIFFRACTION15{ L|* }
16X-RAY DIFFRACTION16{ M|* }

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