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- PDB-8s14: c-KIT kinase domain in complex with sunitinib -

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Basic information

Entry
Database: PDB / ID: 8s14
Titlec-KIT kinase domain in complex with sunitinib
ComponentsMast/stem cell growth factor receptor Kit
KeywordsTRANSFERASE / stem cell factor receptor / inhibitor / GIST / sunitinib / cancer / resistance
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 / 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 / mast cell proliferation / immature B cell differentiation / Developmental Lineage of Mammary Gland Alveolar Cells / melanocyte differentiation / primordial germ cell migration / positive regulation of pseudopodium assembly / positive regulation of long-term neuronal synaptic plasticity / detection of mechanical stimulus involved in sensory perception of sound / erythropoietin-mediated signaling pathway / megakaryocyte development / pigmentation / embryonic hemopoiesis / digestive tract development / Developmental Lineage of Mammary Gland Luminal Epithelial Cells / lamellipodium assembly / Regulation of KIT signaling / somatic stem cell population maintenance / stem cell population maintenance / positive regulation of Notch signaling pathway / positive regulation of tyrosine phosphorylation of STAT protein / growth factor binding / hemopoiesis / cytokine binding / hematopoietic progenitor cell differentiation / T cell differentiation / response to cadmium ion / epithelial cell proliferation / ovarian follicle development / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / B cell differentiation / transmembrane receptor protein tyrosine kinase activity / Transcriptional and post-translational regulation of MITF-M expression and activity / SH2 domain binding / acrosomal vesicle / stem cell differentiation / erythrocyte differentiation / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / mast cell degranulation / positive regulation of receptor signaling pathway via JAK-STAT / cell chemotaxis / male gonad development / visual learning / Signaling by SCF-KIT / receptor protein-tyrosine kinase / cytokine-mediated signaling pathway / cytoplasmic side of plasma membrane / Constitutive Signaling by Aberrant PI3K in Cancer / cell-cell junction / PIP3 activates AKT signaling / regulation of cell population proliferation / regulation of cell shape / protein autophosphorylation / cell migration / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / RAF/MAP kinase cascade / actin cytoskeleton organization / protease binding / protein tyrosine kinase activity / spermatogenesis / positive regulation of MAPK cascade / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / 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 / 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
Chem-B49 / Mast/stem cell growth factor receptor Kit
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.5 Å
AuthorsTeuber, A. / Niggenaber, J. / Landel, I. / Mueller, M.P. / Rauh, D.
Funding support Germany, European Union, 5items
OrganizationGrant numberCountry
German Research Foundation (DFG)RA 1055/3-2 Germany
European Regional Development FundEFRE-800400European Union
German Federal Ministry for Education and Research01ZX2201B Germany
Other governmentNW21-062C
Other privateEx-2021-0033
CitationJournal: To Be Published
Title: c-KIT kinase domain in complex with sunitinib
Authors: Teuber, A. / Niggenaber, J. / Kleinboelting, S.B. / Landel, I. / Warmuth, J. / Busick, D. / Mueller, M.P. / Bauer, S. / Rauh, D.
History
DepositionFeb 15, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 3, 2025Provider: repository / Type: Initial release

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,7525
Polymers37,1941
Non-polymers5584
Water3,549197
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area450 Å2
ΔGint-5 kcal/mol
Surface area14010 Å2
MethodPISA
Unit cell
Length a, b, c (Å)97.770, 69.820, 55.930
Angle α, β, γ (deg.)90.000, 117.000, 90.000
Int Tables number5
Space group name H-MC121
Space group name HallC2y
Symmetry operation#1: x,y,z
#2: -x,y,-z
#3: x+1/2,y+1/2,z
#4: -x+1/2,y+1/2,-z

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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: 37194.430 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KIT, SCFR / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: P10721, receptor protein-tyrosine kinase
#2: Chemical ChemComp-B49 / N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carbo xamide / SUNITINIB


Mass: 398.474 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H27FN4O2 / Feature type: SUBJECT OF INVESTIGATION / Comment: medication, anticancer, inhibitor*YM
#3: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6O2
#4: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 197 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationN

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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: 1.96 Å3/Da / Density % sol: 37.26 %
Crystal growTemperature: 285.15 K / Method: vapor diffusion, hanging drop / pH: 9.5
Details: protein concentration: 6.6 mg/mL, 14 % PEG8000, 20 % ethylene glycole, 100 mM bicine, 30 mM NaI, 30 mM NaBr, 30 mM NaF, pH 9.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.9999 Å
DetectorType: DECTRIS EIGER2 X 16M / Detector: PIXEL / Date: Feb 5, 2020
RadiationMonochromator: SI(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9999 Å / Relative weight: 1
ReflectionResolution: 1.5→43.42 Å / Num. obs: 51247 / % possible obs: 95.3 % / Redundancy: 6.8 % / Biso Wilson estimate: 32.42 Å2 / CC1/2: 0.999 / Net I/σ(I): 16.52
Reflection shellResolution: 1.5→1.6 Å / Num. unique obs: 7429 / CC1/2: 0.57

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Processing

Software
NameVersionClassification
PDB_EXTRACT1.20.1_4487data extraction
PHENIX1.20.1_4487refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.5→43.42 Å / SU ML: 0.312 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 27.7656
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2143 2561 5 %
Rwork0.188 48644 -
obs0.1893 51205 95.5 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 40.84 Å2
Refinement stepCycle: LAST / Resolution: 1.5→43.42 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2376 0 38 197 2611
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00482534
X-RAY DIFFRACTIONf_angle_d0.76443450
X-RAY DIFFRACTIONf_chiral_restr0.051373
X-RAY DIFFRACTIONf_plane_restr0.0064434
X-RAY DIFFRACTIONf_dihedral_angle_d13.5581922
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.5-1.531.0177991.00981872X-RAY DIFFRACTION67.22
1.53-1.560.71961160.77792194X-RAY DIFFRACTION77.86
1.56-1.590.48651330.52282528X-RAY DIFFRACTION88.97
1.59-1.630.42891420.40022709X-RAY DIFFRACTION96.12
1.63-1.670.3331450.32082743X-RAY DIFFRACTION97.47
1.67-1.720.30791450.24012784X-RAY DIFFRACTION98.19
1.72-1.770.26621450.22962750X-RAY DIFFRACTION98.5
1.77-1.820.28361470.23742785X-RAY DIFFRACTION98.95
1.82-1.890.29621470.24992785X-RAY DIFFRACTION99.05
1.89-1.970.25211470.20852809X-RAY DIFFRACTION99.23
1.97-2.050.24511490.19622813X-RAY DIFFRACTION99.26
2.05-2.160.23241480.18972815X-RAY DIFFRACTION99.46
2.16-2.30.22091480.18642823X-RAY DIFFRACTION99.73
2.3-2.480.20361480.18462812X-RAY DIFFRACTION99.7
2.48-2.730.2151500.18352848X-RAY DIFFRACTION99.73
2.73-3.120.18711500.17992836X-RAY DIFFRACTION99.7
3.12-3.930.21871490.16082845X-RAY DIFFRACTION99.87
3.93-43.420.16331530.15962893X-RAY DIFFRACTION99.58
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)
14.13845088512-2.155040805890.8435595050153.08785863465-1.689007455593.750150024610.09188154068660.272881704737-0.029575212799-0.309496242887-0.24006210261-0.1989487483540.4751200572520.6108742618680.1391813214510.294014886690.03910691395870.01984190368690.3286533999720.002108797405080.22915165249421.12793171719.615675844183.89492278735
29.942904242931.318544962545.037484318463.540884507480.4653757443755.89786410198-0.1963068163040.386916339861-0.891860968317-1.051446104740.2640170588820.1412788675410.3691777746830.7951774115620.01480661174070.591448916510.1555380919390.02678728854040.3986789973670.06121161191740.46252455021124.51509577630.3241148608925.61429373577
34.79147181252.552375426681.282607965652.458334257370.2354667652812.918098238290.2267310263520.283558209949-0.320457411335-0.530858967045-0.0971317095669-0.1637682251480.354795422060.143384772979-0.2351933668260.3839119720370.074332323475-0.006756214120430.4526011981490.04541849460340.30986081713619.351230749110.4349392138-0.282664255121
44.21566666999-2.01049602401-1.864800299664.22222523735-0.2073484201883.428073209880.1368279074020.114195516402-0.0909788776143-0.301898386535-0.243395234869-0.2902024766390.2098887626740.5442247564060.1492207562620.2434332143170.05315141719-0.004556350257210.4416950467940.0551687301350.28429389996924.93111624518.3353997514111.2397642186
54.55868163157-0.832917869412.512851619632.588955272320.6817750295318.15724907315-0.141998355134-0.732635825175-0.217487856040.4817729924940.04350003443310.09776349084370.5446420693070.07172902437530.03354513109510.3547579700770.05055364260680.01281562964960.3639793407580.1063203576260.30571507716111.63384876544.355518349933.7002032597
62.812554258480.695156863884-2.011531906645.0784807305-5.310169152887.90423038234-0.0203748644315-0.3397065062310.04013121590350.222696434641-0.240128665756-0.185624123121-0.3289444005240.6982520314560.2395444448930.230993690148-0.0393989045325-0.01678075587340.253240030262-0.01550119335710.24484428345514.392130654818.09028130623.6597545441
74.074344049860.2145546710530.1501983300522.5806207159-1.440118637633.71718706931-0.0178767705996-0.286259110889-0.0891349138329-0.0672916870683-0.0198328804118-0.177960416360.104318176920.3486661295040.1621195260770.2362350984190.01470292221410.015878227530.247836677730.01251934589840.23042030201714.10565765311.540665671917.1793628717
84.257388377250.2036967272840.2287769108792.53771535579-0.6277827352213.20166501087-0.08164778209170.906869060047-0.78215615395-0.5561050627550.122986520633-0.1556401600330.6395501055830.216027678891-0.02092226502560.423455585534-0.005284612122350.01545200548090.348131450353-0.08927233895540.3489518195513.692663530393.907666616319.99749717558
93.02986135361-0.5384394751521.11327304821.51994368655-1.295961553474.0184798199-0.04142509741010.08852776257230.00866665690274-0.2027514363150.09680001259750.0352885816861-0.0716462408691-0.137246963306-0.05219808522260.231906779349-0.02633572818130.01128417709890.176211365938-0.01185930062350.2050267338141.1261591896915.922165033815.9462240826
103.49765636742-0.7033358056741.279674087751.38950761232-0.1739065486973.208763358090.0591015178785-0.341107000529-0.3834441022440.04490943349370.02586687666430.2208522604930.282304991429-0.519950117081-0.1261137957750.249880138901-0.03911779508110.03025785598010.3203957091190.06468082208080.309512444134-6.483418783439.2175154154723.1327404973
116.885685857080.9982265206270.5312080269294.32986167284-0.5939454591778.2127719291-0.0430578728788-0.380997241050.2604848599170.197275448203-0.01291186174570.184934332615-0.432684389133-0.2529622012530.07207704419810.2676347308930.03204814648740.02497267070150.19026826071-0.03587510598610.227882602857-0.95712566920322.499686265223.1352517834
125.718459109930.4509875808480.7684285758486.962455000622.10380247127.569443124870.119269027734-0.590909675030.3702823229270.6693324265910.107153938177-0.13788296427-0.6667987319620.422299328742-0.05261268927730.357935119333-0.0520596704766-0.004877370789190.28267209011-0.07124995515180.29686533257410.950871724925.614995144228.1552485799
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION / Auth asym-ID: A / Label asym-ID: A

IDRefine TLS-IDSelection detailsAuth seq-IDLabel seq-ID
11chain 'A' and (resid 554 through 608 )554 - 6081 - 53
22chain 'A' and (resid 609 through 630 )609 - 63054 - 69
33chain 'A' and (resid 631 through 647 )631 - 64770 - 86
44chain 'A' and (resid 648 through 677 )648 - 67787 - 116
55chain 'A' and (resid 678 through 765 )678 - 765117 - 136
66chain 'A' and (resid 766 through 786 )766 - 786137 - 157
77chain 'A' and (resid 787 through 808 )787 - 808158 - 179
88chain 'A' and (resid 809 through 837 )809 - 837180 - 208
99chain 'A' and (resid 838 through 863 )838 - 863209 - 234
1010chain 'A' and (resid 864 through 896 )864 - 896235 - 267
1111chain 'A' and (resid 897 through 916 )897 - 916268 - 287
1212chain 'A' and (resid 917 through 931 )917 - 931288 - 302

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