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- PDB-8s17: c-KIT kinase domain in complex with ponatinib -

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Basic information

Entry
Database: PDB / ID: 8s17
Titlec-KIT kinase domain in complex with ponatinib
ComponentsMast/stem cell growth factor receptor Kit
KeywordsTRANSFERASE / stem cell factor receptor / GIST / inhibitor / gatekeeper mutation / 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 / hematopoietic stem cell migration / melanocyte adhesion / positive regulation of pyloric antrum smooth muscle contraction / positive regulation of colon smooth muscle contraction / stem cell factor receptor activity / positive regulation of vascular associated smooth muscle cell differentiation / melanocyte migration / Kit signaling pathway / tongue development / regulation of bile acid metabolic process / positive regulation of small intestine smooth muscle contraction / positive regulation of dendritic cell cytokine production / mast cell chemotaxis / positive regulation of mast cell proliferation / mast cell differentiation / Fc receptor signaling pathway / glycosphingolipid metabolic process / mast cell proliferation / positive regulation of pseudopodium assembly / positive regulation of long-term neuronal synaptic plasticity / positive regulation of mast cell cytokine production / lymphoid progenitor cell differentiation / melanocyte differentiation / detection of mechanical stimulus involved in sensory perception of sound / immature B cell differentiation / germ cell migration / erythropoietin-mediated signaling pathway / myeloid progenitor cell differentiation / digestive tract development / negative regulation of programmed cell death / embryonic hemopoiesis / lamellipodium assembly / positive regulation of tyrosine phosphorylation of STAT protein / Regulation of KIT signaling / megakaryocyte development / growth factor binding / mast cell degranulation / stem cell population maintenance / pigmentation / positive regulation of Notch signaling pathway / cytokine binding / negative regulation of reproductive process / negative regulation of developmental process / hemopoiesis / T cell differentiation / somatic stem cell population maintenance / spermatid development / ectopic germ cell programmed cell death / response to cadmium ion / positive regulation of DNA-binding transcription factor activity / hematopoietic progenitor cell differentiation / ovarian follicle development / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / transmembrane receptor protein tyrosine kinase activity / Transcriptional and post-translational regulation of MITF-M expression and activity / acrosomal vesicle / SH2 domain binding / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / B cell differentiation / epithelial cell proliferation / erythrocyte differentiation / cell chemotaxis / positive regulation of receptor signaling pathway via JAK-STAT / stem cell differentiation / Signaling by SCF-KIT / receptor protein-tyrosine kinase / visual learning / cytoplasmic side of plasma membrane / male gonad development / fibrillar center / cytokine-mediated signaling pathway / Constitutive Signaling by Aberrant PI3K in Cancer / cell-cell junction / cell migration / PIP3 activates AKT signaling / regulation of cell shape / regulation of cell population proliferation / protein autophosphorylation / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / RAF/MAP kinase cascade / actin cytoskeleton organization / protease binding / protein tyrosine kinase activity / spermatogenesis / receptor complex / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of MAPK cascade / 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 / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / 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-0LI / Mast/stem cell growth factor receptor Kit
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.2 Å
AuthorsTeuber, A. / 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 ponatinib
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
B: Mast/stem cell growth factor receptor Kit
hetero molecules


Theoretical massNumber of molelcules
Total (without water)75,5968
Polymers74,3892
Non-polymers1,2076
Water3,189177
1
A: Mast/stem cell growth factor receptor Kit
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,8696
Polymers37,1941
Non-polymers6745
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Mast/stem cell growth factor receptor Kit
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,7272
Polymers37,1941
Non-polymers5331
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)88.010, 90.610, 91.410
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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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.: 2
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-0LI / 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzam ide / Ponatinib


Mass: 532.559 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C29H27F3N6O / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Cl
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 177 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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: 2.1 Å3/Da / Density % sol: 41.44 %
Crystal growTemperature: 285.15 K / Method: vapor diffusion, hanging drop / pH: 7
Details: protein concentration: 4 mg/mL, 14% PEG6000, 200 mM LiCl, 100 mM Tris, pH 7.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1.00006 Å
DetectorType: DECTRIS EIGER2 X 16M / Detector: PIXEL / Date: Jun 17, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.00006 Å / Relative weight: 1
ReflectionResolution: 2.2→45.71 Å / Num. obs: 37763 / % possible obs: 100 % / Redundancy: 13.54 % / Biso Wilson estimate: 48.88 Å2 / CC1/2: 0.993 / Net I/σ(I): 10.58
Reflection shellResolution: 2.2→2.3 Å / Num. unique obs: 4621 / CC1/2: 0.684

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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: 2.2→45.31 Å / SU ML: 0.3375 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 27.9819
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2282 1889 5.01 %
Rwork0.2012 35851 -
obs0.2026 37740 99.93 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 59.3 Å2
Refinement stepCycle: LAST / Resolution: 2.2→45.31 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4630 0 82 177 4889
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00244854
X-RAY DIFFRACTIONf_angle_d0.52466592
X-RAY DIFFRACTIONf_chiral_restr0.041701
X-RAY DIFFRACTIONf_plane_restr0.004836
X-RAY DIFFRACTIONf_dihedral_angle_d12.69771753
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.2-2.260.40381440.37972718X-RAY DIFFRACTION99.86
2.26-2.330.3391420.30762706X-RAY DIFFRACTION99.79
2.33-2.40.34291430.26942707X-RAY DIFFRACTION99.93
2.4-2.490.31081430.26282716X-RAY DIFFRACTION99.97
2.49-2.590.2911440.25662747X-RAY DIFFRACTION99.93
2.59-2.70.31261430.25922715X-RAY DIFFRACTION99.97
2.7-2.850.27811450.24382745X-RAY DIFFRACTION99.97
2.85-3.020.29191450.23592745X-RAY DIFFRACTION99.93
3.03-3.260.2661450.22852761X-RAY DIFFRACTION100
3.26-3.590.21591450.20452753X-RAY DIFFRACTION99.97
3.59-4.10.19451470.17532789X-RAY DIFFRACTION99.97
4.11-5.170.16541480.14892814X-RAY DIFFRACTION100
5.17-45.310.19261550.16912935X-RAY DIFFRACTION99.81
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)
10.733709086206-0.5624014941020.4443972790381.337584160830.2151116097181.32094124714-0.132164199399-0.2491012226920.1362182845590.2660484264810.01833346103160.131224359080.0269257072862-0.0160641651760.0873156298440.5550894850450.04901161434950.03509452167870.499414333663-0.02326661967180.473922181925-33.361267902716.2783030758-2.16684399198
20.05824043638670.1657545899420.01255482832840.761737064592-0.7392997309612.00414215469-0.169437003338-0.4119405344970.2393263965130.164033269451-0.09533983406630.738664191243-0.4048040745-0.8322670785990.07063735486550.5350651537680.147055093321-0.05058198879120.695400893794-0.08608433439930.792792909261-46.544186285110.8217925278-3.96905765316
31.61148532724-0.17007013008-1.194356962371.94674820540.8677096465141.55040328521-0.0998484149248-0.09638687474370.08344444616880.3247691000680.135047362329-0.112634160452-0.1334262667950.0269999605187-0.06878849789760.4175532490490.0254065450867-0.01178784758970.3905646050310.006419209480540.357721309208-30.423169677313.1135249609-0.688185997042
42.73610974055-0.37781319268-0.7235675811041.71966714832-0.2539135259121.290471515510.0971578204714-0.04110348809630.2392150920760.04640293576580.01291669374520.137221024605-0.304720613020.0231858869511-0.1181556182910.4331353013220.06923363627010.01833131414710.5104895143590.00253068262410.490074583145-36.635496573316.8292475895-7.07348095998
51.77677191494-0.574414100103-1.120115283542.253500038361.520710439522.60825339912-0.1709364923430.15441543742-0.388951213250.172330509539-0.1196163189330.3881899007310.769421556897-0.3963585140360.1317019732080.489652720873-0.0440621341499-0.05639195038850.455552611809-0.01036172179680.494035127908-36.3694641118-0.258274735101-16.5654240198
60.0003488364414140.009695672675190.001077534850860.1118306621080.07364163464430.0479407239491-0.1288744612571.38528579539-0.4814545778440.3784773216060.1084139559381.321865034631.0264491408-1.83341929265-0.09702194672870.628051783589-0.204271328449-0.05594229631341.0209882988-0.1732209654870.827393742815-41.9261274808-5.88582412949-32.8068975382
71.485861234250.514910811323-0.6570457795922.567202920620.2479814724192.1729971911-0.019144371483-0.0760091498543-0.109165981261-0.04161399447760.06152668422990.02041352529670.03272010478680.144555550248-0.04686053184750.3497192907570.0449929990045-0.009917703877450.401557699262-0.007095670967660.354555202479-22.97426137656.64102553061-17.1970426392
81.485111914220.535090378901-0.6186020192062.71477199950.4599240751642.44506325809-0.03525415548430.110549754349-0.118747739906-0.1359809323760.116703392614-0.5029133379920.2025945674060.428737170256-0.03734831904720.3958999385090.07795809385480.02745054924360.470952447393-0.06389085301450.470759194212-13.90921455680.666834788867-25.8379767223
94.398004601371.988929767070.7855260976464.363403447311.251689906692.505694197520.1881124039620.6895170025050.329992101416-1.05425122825-0.2825345780580.334271237992-0.74972928557-0.252498689055-0.1272760567820.7172104708920.1220122702340.003579373342070.503050797754-0.02359846322590.452467662426-27.021908913412.7274240976-34.4859852988
101.168861113540.8176251338310.6229582790792.817211160870.1771524652782.26672560332-0.3834335737580.001993600382890.489663026238-0.0991513856139-0.002187280882750.105929889104-0.422747869868-0.4703870894490.2052707388820.879670705628-0.03115836501920.03733819689130.540141927259-0.0578687238380.659634243072-56.367490578920.1303866812-22.6954902657
112.097117980681.287649535570.4800156085293.58882105920.5570332149340.906255028176-0.0714192809604-0.01832591694550.298064906432-0.05783337515010.0269148392327-0.462300935816-0.2091047696220.100375904639-0.06323961892470.6853429981210.006319756794260.02200505672920.5433636365620.007609290789710.666830477317-56.89248968489.76421774597-20.7130786934
122.59934702260.3361756051911.501349180311.86354655689-1.25158193182.478332567060.335574868307-0.2506739315450.01216672482281.17154632628-0.318487486179-0.0645072282417-0.1887935360140.207753628916-0.05914094798930.740878906604-0.0536740745583-0.02439844282490.547159642813-0.02986220372870.476778787832-62.5726721376-4.04213153957-10.1819372747
131.95748153831.53086596170.3388629079215.06090197720.4042824083492.26607792922-0.0294709738333-0.02257258266760.2477042625880.09481908637650.0823741297150.272077531317-0.0990748025409-0.139308607674-0.02689304607610.4317914208920.03765224995620.01835655489750.4540367087270.009634826211140.460785137129-69.3242424073-7.45950779927-21.5057227928
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION

IDRefine TLS-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11chain 'A' and (resid 567 through 600 )AA567 - 6001 - 34
22chain 'A' and (resid 601 through 617 )AA601 - 61735 - 51
33chain 'A' and (resid 618 through 647 )AA618 - 64752 - 81
44chain 'A' and (resid 648 through 666 )AA648 - 66682 - 100
55chain 'A' and (resid 667 through 688 )AA667 - 688101 - 122
66chain 'A' and (resid 689 through 765 )AA689 - 765123 - 139
77chain 'A' and (resid 766 through 863 )AA766 - 863140 - 237
88chain 'A' and (resid 864 through 916 )AA864 - 916238 - 290
99chain 'A' and (resid 917 through 931 )AA917 - 931291 - 305
1010chain 'B' and (resid 578 through 600 )BC578 - 6001 - 23
1111chain 'B' and (resid 601 through 765 )BC601 - 76524 - 118
1212chain 'B' and (resid 766 through 785 )BC766 - 785119 - 138
1313chain 'B' and (resid 786 through 931 )BC786 - 931139 - 284

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