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- PDB-8pq9: c-KIT kinase domain in complex with avapritinib -

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Basic information

Entry
Database: PDB / ID: 8pq9
Titlec-KIT kinase domain in complex with avapritinib
ComponentsMast/stem cell growth factor receptor Kit
KeywordsTRANSFERASE / c-KIT protein kinase / avapritinib / inhibitor / tyrosine kinase / transmembrane receptor / stem cell factor / SCF / stem cell factor receptor / GIST / gastrointestinal stromal tumors / P10721
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 / positive regulation of mast cell cytokine production / immature B cell differentiation / melanocyte differentiation / germ cell migration / lymphoid progenitor cell differentiation / myeloid progenitor cell differentiation / digestive tract development / negative regulation of programmed cell death / embryonic hemopoiesis / lamellipodium assembly / pigmentation / tongue development / megakaryocyte development / Regulation of KIT signaling / mast cell degranulation / stem cell population maintenance / positive regulation of Notch signaling pathway / cytokine binding / negative regulation of reproductive process / negative regulation of developmental process / spermatid development / growth factor binding / somatic stem cell population maintenance / hemopoiesis / T cell differentiation / ectopic germ cell programmed cell death / hematopoietic progenitor cell differentiation / positive regulation of phospholipase C activity / 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 / cell chemotaxis / B cell differentiation / erythrocyte differentiation / acrosomal vesicle / 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 / cytoplasmic side of plasma membrane / receptor protein-tyrosine kinase / fibrillar center / cytokine-mediated signaling pathway / male gonad development / Constitutive Signaling by Aberrant PI3K in Cancer / positive regulation of DNA-binding transcription factor activity / 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 / protein tyrosine kinase activity / protease binding / 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 / inflammatory response
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 / Tyrosine protein kinases specific active-site signature. ...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-9JI / Mast/stem cell growth factor receptor Kit
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.7 Å
AuthorsTeuber, A. / Kleinboelting, S. / Mueller, M.P. / Rauh, D.
Funding supportEuropean Union, Germany, 4items
OrganizationGrant numberCountry
European Regional Development FundEFRE-800400European Union
German Federal Ministry for Education and Research01ZX2201B Germany
Other privateEx-2021-0033
Other governmentNW21-062C
CitationJournal: Nat Commun / Year: 2024
Title: Avapritinib-based SAR studies unveil a binding pocket in KIT and PDGFRA.
Authors: Teuber, A. / Schulz, T. / Fletcher, B.S. / Gontla, R. / Muhlenberg, T. / Zischinsky, M.L. / Niggenaber, J. / Weisner, J. / Kleinbolting, S.B. / Lategahn, J. / Sievers, S. / Muller, M.P. / Bauer, S. / Rauh, D.
History
DepositionJul 11, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 27, 2023Provider: repository / Type: Initial release
Revision 1.1Jan 17, 2024Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Mar 13, 2024Group: Database references / Category: pdbx_related_exp_data_set

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


Theoretical massNumber of molelcules
Total (without water)75,4825
Polymers74,3892
Non-polymers1,0933
Water8,755486
1
A: Mast/stem cell growth factor receptor Kit
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,6932
Polymers37,1941
Non-polymers4991
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
C: Mast/stem cell growth factor receptor Kit
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,7893
Polymers37,1941
Non-polymers5952
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)59.020, 59.300, 191.760
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-9JI / (1~{S})-1-(4-fluorophenyl)-1-[2-[4-[6-(1-methylpyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]piperazin-1-yl]pyrimidin-5-yl]ethanamine


Mass: 498.558 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C26H27FN10 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 486 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 1.93 Å3/Da / Density % sol: 36.4 %
Crystal growTemperature: 285.15 K / Method: vapor diffusion, hanging drop / pH: 8.5
Details: 6.6 mg/mL, 10% PEG8000, 20% Ethylen glycole, 30 mM NaI, 30 mM NaF, 30 mM NaBr, 100 mM Bicine, pH 8.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.9998 Å
DetectorType: DECTRIS EIGER2 X 16M / Detector: PIXEL / Date: Aug 23, 2021
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9998 Å / Relative weight: 1
ReflectionResolution: 1.7→47.94 Å / Num. obs: 74995 / % possible obs: 100 % / Redundancy: 13.37 % / Biso Wilson estimate: 34.44 Å2 / CC1/2: 0.999 / Rrim(I) all: 0.057 / Net I/σ(I): 22.42
Reflection shellResolution: 1.7→1.8 Å / Redundancy: 13.43 % / Mean I/σ(I) obs: 1.89 / Num. unique obs: 11621 / CC1/2: 0.895 / Rrim(I) all: 1.391 / % possible all: 99.9

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
PDB_EXTRACTdata extraction
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.7→35 Å / SU ML: 0.2712 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 24.9594
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2044 3745 5 %
Rwork0.1905 71175 -
obs0.1912 74920 99.88 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 41.49 Å2
Refinement stepCycle: LAST / Resolution: 1.7→35 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4610 0 79 486 5175
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00594883
X-RAY DIFFRACTIONf_angle_d0.87326654
X-RAY DIFFRACTIONf_chiral_restr0.0546719
X-RAY DIFFRACTIONf_plane_restr0.0064915
X-RAY DIFFRACTIONf_dihedral_angle_d5.2374744
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.7-1.720.49941340.50682560X-RAY DIFFRACTION99.74
1.72-1.740.52911400.44952649X-RAY DIFFRACTION99.57
1.74-1.770.42211330.40122539X-RAY DIFFRACTION99.78
1.77-1.790.34171390.33462649X-RAY DIFFRACTION99.79
1.79-1.820.34621350.30942566X-RAY DIFFRACTION99.7
1.82-1.850.3031390.27292625X-RAY DIFFRACTION99.82
1.85-1.880.27291340.24212549X-RAY DIFFRACTION99.74
1.88-1.910.271400.23872658X-RAY DIFFRACTION99.79
1.91-1.950.2851350.22322585X-RAY DIFFRACTION99.78
1.95-1.980.26781370.22182598X-RAY DIFFRACTION99.82
1.98-2.020.28121360.22442594X-RAY DIFFRACTION99.93
2.02-2.070.25491380.24052620X-RAY DIFFRACTION99.78
2.07-2.120.23261380.22642622X-RAY DIFFRACTION99.86
2.12-2.170.2221370.19832601X-RAY DIFFRACTION99.96
2.17-2.230.21841380.19972622X-RAY DIFFRACTION99.93
2.23-2.290.28681400.2032646X-RAY DIFFRACTION99.96
2.29-2.370.25221390.19762650X-RAY DIFFRACTION99.96
2.37-2.450.22231390.19922631X-RAY DIFFRACTION100
2.45-2.550.24081380.20042621X-RAY DIFFRACTION100
2.55-2.670.20691380.20072621X-RAY DIFFRACTION100
2.67-2.810.20411400.1942671X-RAY DIFFRACTION100
2.81-2.980.23141410.19462670X-RAY DIFFRACTION100
2.98-3.210.20511390.19152648X-RAY DIFFRACTION100
3.21-3.540.1931410.18082685X-RAY DIFFRACTION100
3.54-4.050.1611420.15012682X-RAY DIFFRACTION100
4.05-5.090.15071440.14552748X-RAY DIFFRACTION100
5.1-350.16381510.18412865X-RAY DIFFRACTION99.77
Refinement TLS params.Method: refined / Origin x: -2.43367472488 Å / Origin y: -4.21608035148 Å / Origin z: 23.5750787235 Å
111213212223313233
T0.247590294691 Å20.040388307382 Å2-0.0342382203611 Å2-0.24616995271 Å2-0.0107374522085 Å2--0.260943093856 Å2
L0.256683495248 °20.0995473370235 °2-0.352754200123 °2-0.120935235332 °2-0.179589673054 °2--0.83247269251 °2
S0.0228852638894 Å °-0.00922851909084 Å °0.0214008244784 Å °0.018711929949 Å °0.00193496870531 Å °0.0149856881714 Å °-0.115454063633 Å °-0.108574268826 Å °-0.0216070580743 Å °
Refinement TLS groupSelection details: all

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