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- PDB-6itv: Crystal structure of activated c-KIT in complex with compound -

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Basic information

Entry
Database: PDB / ID: 6itv
TitleCrystal structure of activated 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 / stem cell factor receptor activity / hematopoietic stem cell migration / melanocyte adhesion / positive regulation of pyloric antrum smooth muscle contraction / positive regulation of colon smooth muscle contraction / erythropoietin-mediated signaling pathway / positive regulation of vascular associated smooth muscle cell differentiation / melanocyte migration / positive regulation of dendritic cell cytokine production / Kit signaling pathway / regulation of bile acid metabolic process / positive regulation of small intestine smooth muscle contraction / mast cell differentiation / positive regulation of mast cell proliferation / mast cell chemotaxis / Fc receptor signaling pathway / glycosphingolipid metabolic process / mast cell proliferation / positive regulation of long-term neuronal synaptic plasticity / detection of mechanical stimulus involved in sensory perception of sound / positive regulation of pseudopodium assembly / immature B cell differentiation / melanocyte differentiation / positive regulation of mast cell cytokine production / lymphoid progenitor cell differentiation / germ cell migration / myeloid progenitor cell differentiation / digestive tract development / negative regulation of programmed cell death / embryonic hemopoiesis / lamellipodium assembly / tongue development / megakaryocyte development / Regulation of KIT signaling / stem cell population maintenance / pigmentation / mast cell degranulation / positive regulation of Notch signaling pathway / negative regulation of reproductive process / negative regulation of developmental process / growth factor binding / cytokine binding / somatic stem cell population maintenance / hemopoiesis / spermatid development / T cell differentiation / Transcriptional and post-translational regulation of MITF-M expression and activity / ectopic germ cell programmed cell death / hematopoietic progenitor cell differentiation / : / response to cadmium ion / ovarian follicle development / positive regulation of tyrosine phosphorylation of STAT protein / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / transmembrane receptor protein tyrosine kinase activity / SH2 domain binding / B cell differentiation / cell chemotaxis / acrosomal vesicle / erythrocyte differentiation / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / epithelial cell proliferation / stem cell differentiation / positive regulation of receptor signaling pathway via JAK-STAT / visual learning / Signaling by SCF-KIT / receptor protein-tyrosine kinase / cytoplasmic side of plasma membrane / fibrillar center / positive regulation of DNA-binding transcription factor activity / cytokine-mediated signaling pathway / Constitutive Signaling by Aberrant PI3K in Cancer / male gonad development / cell-cell junction / PIP3 activates AKT signaling / regulation of cell population proliferation / regulation of cell shape / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / actin cytoskeleton organization / RAF/MAP kinase cascade / spermatogenesis / protease binding / protein tyrosine kinase activity / positive regulation of MAPK cascade / protein autophosphorylation / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor complex / intracellular signal transduction / positive regulation of cell migration
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 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; 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: 1.881 Å
AuthorsWu, T.S. / Wu, S.Y.
CitationJournal: To Be Published
Title: Crystal structure of activated 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)38,2652
Polymers37,7501
Non-polymers5161
Water4,089227
1
A: Mast/stem cell growth factor receptor Kit
hetero molecules

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


Theoretical massNumber of molelcules
Total (without water)76,5304
Polymers75,4992
Non-polymers1,0312
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation7_645y+1,x-1,-z1
Buried area2350 Å2
ΔGint-3 kcal/mol
Surface area27520 Å2
MethodPISA
Unit cell
Length a, b, c (Å)59.853, 59.853, 197.984
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number96
Space group name H-MP43212

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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: 37749.535 Da / Num. of mol.: 1
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 / Production host: unidentified baculovirus
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.: 1 / Source method: obtained synthetically / Formula: C25H25N9O2S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 227 / 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: 2.35 Å3/Da / Density % sol: 47.63 %
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, 3% 1,6-hexanediol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: NSRRC / Beamline: BL15A1 / Wavelength: 1 Å
DetectorType: RAYONIX MX300HE / Detector: CCD / Date: Apr 18, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.88→30 Å / Num. obs: 30279 / % possible obs: 99.7 % / Redundancy: 5.1 % / Biso Wilson estimate: 30.42 Å2 / Rmerge(I) obs: 0.055 / Rpim(I) all: 0.027 / Rrim(I) all: 0.062 / Χ2: 1.051 / Net I/σ(I): 13.7 / Num. measured all: 154364
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
1.88-1.955.20.65429350.8570.3180.7291.059100
1.95-2.035.20.44729770.9420.2170.4981.071100
2.03-2.125.20.31129670.9690.1510.3471.05100
2.12-2.235.20.22430070.980.1080.251.05100
2.23-2.375.20.16229670.9880.0780.1811.075100
2.37-2.555.10.12330020.9920.060.1371.05100
2.55-2.815.10.07830220.9960.0380.0871.011100
2.81-3.215.10.05430590.9970.0260.061.031100
3.21-4.054.90.0431130.9980.020.0451.057100
4.05-304.80.02532300.9990.0120.0271.0697

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Processing

Software
NameVersionClassification
HKL-2000data scaling
PHENIXdev_2621refinement
PDB_EXTRACT3.24data extraction
RefinementResolution: 1.881→26.767 Å / SU ML: 0.19 / Cross valid method: THROUGHOUT / σ(F): 1.33 / Phase error: 24.06
RfactorNum. reflection% reflection
Rfree0.2306 1999 6.63 %
Rwork0.1798 --
obs0.1832 30161 99.59 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 126.92 Å2 / Biso mean: 42.0495 Å2 / Biso min: 20.67 Å2
Refinement stepCycle: final / Resolution: 1.881→26.767 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2372 0 37 227 2636
Biso mean--31.4 48.17 -
Num. residues----298
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0062482
X-RAY DIFFRACTIONf_angle_d0.8283362
X-RAY DIFFRACTIONf_chiral_restr0.052363
X-RAY DIFFRACTIONf_plane_restr0.005423
X-RAY DIFFRACTIONf_dihedral_angle_d11.352045
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 (%)
1.8808-1.92780.31541400.270919852125100
1.9278-1.97990.30081390.235819332072100
1.9799-2.03810.23961390.224119612100100
2.0381-2.10390.26961410.206519822123100
2.1039-2.17910.28771410.198519862127100
2.1791-2.26630.23241410.188219892130100
2.2663-2.36930.24171420.185419872129100
2.3693-2.49420.24271420.183920162158100
2.4942-2.65030.22121410.192519862127100
2.6503-2.85470.2451430.200720262169100
2.8547-3.14160.25041450.19520332178100
3.1416-3.59530.21231440.175920382182100
3.5953-4.52610.17271480.14520832231100
4.5261-26.76980.25661530.16742157231096
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)
13.4236-0.2025-0.355.626-0.44653.3779-0.0801-0.03450.3158-0.16730.07-0.0681-0.2091-0.0064-0.00390.1851-0.0153-0.06740.2439-0.00860.11538.711-7.3763-28.6497
22.37030.0181-1.44233.72431.51473.72520.00050.03630.0203-0.23720.0086-0.1135-0.06340.0721-0.01510.1898-0.0152-0.00130.15970.01940.179238.9635-10.4474-27.1716
33.0761-1.76130.94191.7344-0.17928.1551-0.2291-0.6613-0.63340.08870.0240.20980.9694-0.28410.20160.3508-0.03320.0080.229-0.00030.312231.8508-20.5273-11.3654
42.4209-0.4410.53633.4805-5.5689.5546-0.0534-0.358-0.06180.16720.1182-0.04990.0822-0.2022-0.10160.24980.0066-0.00070.2771-0.04690.219533.4637-10.7484-1.6693
52.3387-0.6615-1.01292.64960.39382.8680.01880.33310.0653-0.2796-0.01730.3534-0.1435-0.71350.00370.22170.0033-0.04830.35630.02360.244722.8254-7.9311-14.5154
66.1401-0.960.27793.26211.21222.97010.17690.0724-0.1646-0.2276-0.05010.67840.0684-1.0631-0.16920.2333-0.01210.01650.58410.02310.413411.1849-10.0351-5.0172
74.16590.45930.15965.6699-3.92895.96940.1355-0.09890.21230.29860.17060.3616-0.6017-0.5266-0.27790.25960.08150.04610.2887-0.03570.251320.32370.1387-0.2924
84.8088-3.72093.45265.6358-4.99224.47-0.2263-0.52310.00051.13170.0647-0.4246-0.35750.30190.17950.5136-0.0323-0.0320.3931-0.07470.282333.6921-4.38856.0944
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 569 through 600 )A569 - 600
2X-RAY DIFFRACTION2chain 'A' and (resid 601 through 666 )A601 - 666
3X-RAY DIFFRACTION3chain 'A' and (resid 667 through 758 )A667 - 758
4X-RAY DIFFRACTION4chain 'A' and (resid 759 through 786 )A759 - 786
5X-RAY DIFFRACTION5chain 'A' and (resid 787 through 863 )A787 - 863
6X-RAY DIFFRACTION6chain 'A' and (resid 864 through 896 )A864 - 896
7X-RAY DIFFRACTION7chain 'A' and (resid 897 through 916 )A897 - 916
8X-RAY DIFFRACTION8chain 'A' and (resid 917 through 935 )A917 - 935

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