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- PDB-6itt: Crystal structure of unactivated c-KIT in complex with compound -

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Basic information

Entry
Database: PDB / ID: 6itt
TitleCrystal structure of unactivated c-KIT in complex with compound
ComponentsMast/stem cell growth factor receptor Kit
KeywordsONCOPROTEIN / Receptor tyrosine kinase DFG motif conformational control inhibitor
Function / homology
Function and homology information


Dasatinib-resistant KIT mutants / Imatinib-resistant KIT mutants / KIT mutants bind TKIs / Masitinib-resistant KIT mutants / Nilotinib-resistant KIT mutants / Regorafenib-resistant KIT mutants / Signaling by kinase domain mutants of KIT / Sunitinib-resistant KIT mutants / Signaling by juxtamembrane domain KIT mutants / Sorafenib-resistant KIT mutants ...Dasatinib-resistant KIT mutants / Imatinib-resistant KIT mutants / KIT mutants bind TKIs / Masitinib-resistant KIT mutants / Nilotinib-resistant KIT mutants / Regorafenib-resistant KIT mutants / Signaling by kinase domain mutants of KIT / Sunitinib-resistant KIT mutants / Signaling by juxtamembrane domain KIT mutants / Sorafenib-resistant KIT mutants / Signaling by extracellular domain mutants of KIT / melanocyte adhesion / positive regulation of pyloric antrum smooth muscle contraction / positive regulation of colon smooth muscle contraction / melanocyte migration / stem cell factor receptor activity / mast cell proliferation / positive regulation of vascular associated smooth muscle cell differentiation / Kit signaling pathway / positive regulation of dendritic cell cytokine production / tongue development / positive regulation of small intestine smooth muscle contraction / positive regulation of mast cell cytokine production / mast cell differentiation / mast cell chemotaxis / Fc receptor signaling pathway / immature B cell differentiation / epithelial cell proliferation / melanocyte differentiation / positive regulation of long-term neuronal synaptic plasticity / primordial germ cell migration / positive regulation of pseudopodium assembly / detection of mechanical stimulus involved in sensory perception of sound / megakaryocyte development / erythropoietin-mediated signaling pathway / somatic stem cell population maintenance / pigmentation / embryonic hemopoiesis / digestive tract development / lamellipodium assembly / Regulation of KIT signaling / stem cell population maintenance / positive regulation of Notch signaling pathway / growth factor binding / positive regulation of tyrosine phosphorylation of STAT protein / Developmental Lineage of Mammary Gland Alveolar Cells / ovarian follicle development / hemopoiesis / cytokine binding / hematopoietic progenitor cell differentiation / T cell differentiation / Developmental Lineage of Mammary Gland Luminal Epithelial Cells / response to cadmium ion / B cell differentiation / stem cell differentiation / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / transmembrane receptor protein tyrosine kinase activity / male gonad development / Transcriptional and post-translational regulation of MITF-M expression and activity / visual learning / acrosomal vesicle / SH2 domain binding / erythrocyte differentiation / positive regulation of receptor signaling pathway via JAK-STAT / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / mast cell degranulation / cell chemotaxis / Signaling by SCF-KIT / receptor protein-tyrosine kinase / cytokine-mediated signaling pathway / Constitutive Signaling by Aberrant PI3K in Cancer / cytoplasmic side of plasma membrane / regulation of cell shape / cell-cell junction / actin cytoskeleton organization / PIP3 activates AKT signaling / regulation of cell population proliferation / protein autophosphorylation / cell migration / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / RAF/MAP kinase cascade / protease binding / protein tyrosine kinase activity / spermatogenesis / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of MAPK cascade / signaling receptor complex / positive regulation of cell migration / inflammatory response / external side of plasma membrane / positive regulation of cell population proliferation / signal transduction / protein homodimerization activity / : / ATP binding / metal ion binding / plasma membrane
Similarity search - Function
Mast/stem cell growth factor receptor / Tyrosine-protein kinase, receptor class III, conserved site / Receptor tyrosine kinase class III signature. / Immunoglobulin / Immunoglobulin domain / : / Immunoglobulin subtype 2 / Immunoglobulin C-2 Type / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain ...Mast/stem cell growth factor receptor / Tyrosine-protein kinase, receptor class III, conserved site / Receptor tyrosine kinase class III signature. / Immunoglobulin / Immunoglobulin domain / : / Immunoglobulin subtype 2 / Immunoglobulin C-2 Type / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / Immunoglobulin subtype / Immunoglobulin / Tyrosine-protein kinase, active site / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / 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-AWO / Mast/stem cell growth factor receptor Kit
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.103 Å
AuthorsWu, T.S. / Wu, S.Y.
CitationJournal: To Be Published
Title: Crystal structure of unactivated c-KIT in complex with compound
Authors: Wu, T.S. / Wu, S.Y.
History
DepositionNov 26, 2018Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Nov 27, 2019Provider: repository / Type: Initial release
Revision 1.1Mar 27, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Mast/stem cell growth factor receptor Kit
B: Mast/stem cell growth factor receptor Kit
hetero molecules


Theoretical massNumber of molelcules
Total (without water)76,3704
Polymers75,3392
Non-polymers1,0312
Water4,234235
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: mass spectrometry
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1830 Å2
ΔGint2 kcal/mol
Surface area28760 Å2
Unit cell
Length a, b, c (Å)62.629, 63.087, 196.812
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Mast/stem cell growth factor receptor Kit / SCFR / Piebald trait protein / PBT / Proto-oncogene c-Kit / Tyrosine-protein kinase Kit / p145 c- ...SCFR / Piebald trait protein / PBT / Proto-oncogene c-Kit / Tyrosine-protein kinase Kit / p145 c-kit / v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog


Mass: 37669.559 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Details: kinase domain, residue 547-693 and 754-935 from UNP P10721, linked with TS
Source: (gene. exp.) Homo sapiens (human) / Gene: KIT, SCFR / Plasmid: Baculovirus / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P10721, receptor protein-tyrosine kinase
#2: Chemical ChemComp-AWO / N-(5-ethyl-1,2-oxazol-3-yl)-N'-[4-(2-{[6-(4-ethylpyrazin-1(4H)-yl)pyrimidin-4-yl]amino}-1,3-thiazol-5-yl)phenyl]urea


Mass: 515.590 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C25H25N9O2S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 235 / 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: 2.58 Å3/Da / Density % sol: 56.89 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop
Details: 15% PEG 3350, 0.1M sodium citrate tribasic dihydrate, pH 5.6, 3% ethylene glycol, 2% benzamidine hydrochloride

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SPring-8 / Beamline: BL44XU / Wavelength: 0.9 Å
DetectorType: RAYONIX MX300HE / Detector: CCD / Date: Jul 25, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9 Å / Relative weight: 1
ReflectionResolution: 2.1→30 Å / Num. obs: 45999 / % possible obs: 99.5 % / Redundancy: 3.5 % / Biso Wilson estimate: 36.66 Å2 / Rmerge(I) obs: 0.057 / Rpim(I) all: 0.036 / Rrim(I) all: 0.068 / Χ2: 1.066 / Net I/σ(I): 11
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
2.1-2.183.50.59645480.7610.3650.7011.054100
2.18-2.263.50.46645320.8160.2890.551.08699.9
2.26-2.373.50.30145400.920.1850.3551.085100
2.37-2.493.50.21245880.9550.130.2491.062100
2.49-2.653.50.15645590.9730.0960.1841.068100
2.65-2.853.50.11646090.9840.0720.1361.07699.9
2.85-3.143.50.07346040.9930.0450.0861.07599.9
3.14-3.593.50.04446110.9960.0280.0521.05799.7
3.59-4.523.30.03546640.9980.0220.0411.06799
4.52-303.30.02447440.9990.0150.0281.03396.5

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Processing

Software
NameVersionClassification
HKL-2000data scaling
PHENIXdev_2621refinement
PDB_EXTRACT3.24data extraction
RefinementResolution: 2.103→28.428 Å / SU ML: 0.24 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 24.02
RfactorNum. reflection% reflection
Rfree0.2346 2011 4.38 %
Rwork0.1862 --
obs0.1883 45932 99.3 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 160.47 Å2 / Biso mean: 57.5929 Å2 / Biso min: 23.51 Å2
Refinement stepCycle: final / Resolution: 2.103→28.428 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4754 0 74 235 5063
Biso mean--48.5 51.28 -
Num. residues----598
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0084952
X-RAY DIFFRACTIONf_angle_d0.9766699
X-RAY DIFFRACTIONf_chiral_restr0.054723
X-RAY DIFFRACTIONf_plane_restr0.006845
X-RAY DIFFRACTIONf_dihedral_angle_d12.3033516
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 14

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.1028-2.15530.311360.26683028316497
2.1553-2.21360.29321450.239330553200100
2.2136-2.27870.29751390.242331313270100
2.2787-2.35220.26391400.215731223262100
2.3522-2.43630.25211440.214731373281100
2.4363-2.53370.29471370.204931193256100
2.5337-2.6490.26021430.211631203263100
2.649-2.78850.26751440.212531333277100
2.7885-2.96310.27621450.214731623307100
2.9631-3.19160.25461460.203531443290100
3.1916-3.51220.24781470.186631633310100
3.5122-4.01920.21411420.16443166330899
4.0192-5.05910.18791530.14693190334399
5.0591-28.43070.19511500.16623251340196
Refinement TLS params.

Method: refined / 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)
14.3987-0.10530.74761.39010.11383.74820.04240.3610.1838-1.1407-0.16220.5761-0.4054-0.13090.15430.81110.0072-0.27090.2636-0.02410.4328-31.7142-2.2658-50.4554
27.49216.06235.12716.16655.41724.76640.1331-0.1235-0.3171-0.03880.3191-0.9434-0.10451.0189-0.43210.5091-0.0747-0.01720.4656-0.01640.3541-13.9192-5.1548-41.0722
35.6330.3838-2.61722.3622-2.12213.2243-0.65450.0661-0.82530.108-0.2738-0.35960.4318-0.09420.86010.45580.034-0.04770.5807-0.22250.954210.99569.0192-7.3935
41.0078-0.16290.39480.748-0.81992.1109-0.6881.0056-0.2161-0.94130.6007-0.9503-0.30631.12450.05730.6634-0.52710.30731.1571-0.25280.7086.503115.2738-27.9381
56.11093.68980.45355.18080.47813.7848-0.5390.67820.1278-0.80780.34050.5167-0.6803-0.02920.20460.4717-0.1635-0.10620.4378-0.00830.3477-14.461914.8777-23.574
61.61991.84322.80684.82921.79815.6807-0.08120.2682-0.3569-0.11220.2090.10810.31130.0521-0.08580.2601-0.09910.05230.3592-0.11940.2848-14.04495.1225-14.8939
72.33071.12140.39582.74891.5262.4107-0.29550.0760.3156-0.38220.411-0.2096-0.50860.6354-0.06160.2963-0.1364-0.0090.449-0.1180.3802-6.186819.2381-10.7074
83.31291.4056-1.52414.7166-1.26592.2917-0.0077-0.37560.8991-0.0418-0.14681.0647-0.4265-0.10860.15130.23710.0233-0.06780.4054-0.17960.5866-17.770423.5576-2.0295
96.52392.8022.65322.27973.35546.92010.1992-0.476-0.04630.5991-0.08830.14650.4485-0.022-0.1080.25530.0440.01280.3781-0.07760.2734-12.960110.27131.3213
109.2464.9973.05838.22773.21882.1671-0.37230.8193-1.38230.26210.3365-0.22630.95080.1789-0.02680.44650.00260.08730.4914-0.12130.5272-14.2497-1.1297-6.9705
111.81281.39550.06474.64620.83793.29590.516-0.619-0.2590.419-0.37250.21411.0804-0.3676-0.15260.9202-0.2701-0.17660.63010.09190.5376-34.7398-23.4469-24.8029
124.4882-2.71091.64865.8311-0.66585.68670.1794-1.33250.32281.6296-0.5502-0.22780.49940.02710.10861.1644-0.5647-0.02641.03360.11440.5664-32.1246-16.0276-11.8665
134.07012.2687-0.90342.9319-0.11221.03690.4147-0.4873-0.06110.4879-0.40950.3930.9993-0.50640.01430.865-0.4338-0.14520.61090.05640.5384-36.1804-21.3965-24.2083
145.5832.21350.47881.42971.70024.04610.2509-0.51340.77870.2115-0.68920.6606-0.245-0.42690.37960.4118-0.1202-0.04030.4224-0.15490.4694-31.7148-0.9074-26.4426
154.86542.88981.43075.85982.35114.52940.2055-0.17560.30430.2938-0.2248-0.1819-0.17250.31120.01960.3782-0.0907-0.11080.29410.02270.2516-20.8941-2.6022-34.2786
161.49910.98070.81053.43760.61664.11390.3599-0.32810.0002-0.171-0.23210.65730.4636-0.7733-0.10750.4217-0.1531-0.12760.4097-0.03460.5293-37.3906-10.0183-35.7002
174.36063.6492.70415.42913.20383.29610.1491-0.0444-0.0007-0.4139-0.27380.60220.0557-0.16860.10160.5364-0.0287-0.17810.2234-0.02030.3997-32.2208-10.4736-45.7514
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'B' and (resid 864 through 916 )B864 - 916
2X-RAY DIFFRACTION2chain 'B' and (resid 917 through 932 )B917 - 932
3X-RAY DIFFRACTION3chain 'A' and (resid 563 through 579 )A563 - 579
4X-RAY DIFFRACTION4chain 'A' and (resid 580 through 666 )A580 - 666
5X-RAY DIFFRACTION5chain 'A' and (resid 667 through 759 )A667 - 759
6X-RAY DIFFRACTION6chain 'A' and (resid 760 through 786 )A760 - 786
7X-RAY DIFFRACTION7chain 'A' and (resid 787 through 863 )A787 - 863
8X-RAY DIFFRACTION8chain 'A' and (resid 864 through 896 )A864 - 896
9X-RAY DIFFRACTION9chain 'A' and (resid 897 through 916 )A897 - 916
10X-RAY DIFFRACTION10chain 'A' and (resid 917 through 932 )A917 - 932
11X-RAY DIFFRACTION11chain 'B' and (resid 566 through 600 )B566 - 600
12X-RAY DIFFRACTION12chain 'B' and (resid 601 through 616 )B601 - 616
13X-RAY DIFFRACTION13chain 'B' and (resid 617 through 666 )B617 - 666
14X-RAY DIFFRACTION14chain 'B' and (resid 667 through 758 )B667 - 758
15X-RAY DIFFRACTION15chain 'B' and (resid 759 through 786 )B759 - 786
16X-RAY DIFFRACTION16chain 'B' and (resid 787 through 837 )B787 - 837
17X-RAY DIFFRACTION17chain 'B' and (resid 838 through 863 )B838 - 863

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