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- PDB-8pqc: c-KIT kinase domain in complex with avapritinib derivative 9 -

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Basic information

Entry
Database: PDB / ID: 8pqc
Titlec-KIT kinase domain in complex with avapritinib derivative 9
ComponentsMast/stem cell growth factor receptor Kit
KeywordsTRANSFERASE / c-KIT / protein kinase / avapritinib / inhibitor / tyrosine kinase / transmembrane receptor / stem cell factor / 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 / positive regulation of vascular associated smooth muscle cell differentiation / melanocyte migration / Kit signaling pathway / positive regulation of dendritic cell cytokine production / 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 / detection of mechanical stimulus involved in sensory perception of sound / positive regulation of pseudopodium assembly / positive regulation of long-term neuronal synaptic plasticity / immature B cell differentiation / positive regulation of mast cell cytokine production / lymphoid progenitor cell differentiation / melanocyte differentiation / germ cell migration / myeloid progenitor cell differentiation / erythropoietin-mediated signaling pathway / digestive tract development / negative regulation of programmed cell death / embryonic hemopoiesis / lamellipodium assembly / tongue development / pigmentation / megakaryocyte development / Regulation of KIT signaling / stem cell population maintenance / 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 / ectopic germ cell programmed cell death / hematopoietic progenitor cell differentiation / Transcriptional and post-translational regulation of MITF-M expression and 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 / B cell differentiation / cell chemotaxis / acrosomal vesicle / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / erythrocyte differentiation / epithelial cell proliferation / stem cell differentiation / positive regulation of DNA-binding transcription factor activity / positive regulation of receptor signaling pathway via JAK-STAT / visual learning / Signaling by SCF-KIT / receptor protein-tyrosine kinase / fibrillar center / cytokine-mediated signaling pathway / cytoplasmic side of plasma membrane / 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 / protein autophosphorylation / positive regulation of MAPK cascade / 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 ...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-9OO / Mast/stem cell growth factor receptor Kit
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.77 Å
AuthorsTeuber, A. / Kleinboelting, S.B. / 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
Revision 1.3Aug 7, 2024Group: Database references / Category: pdbx_related_exp_data_set / Item: _pdbx_related_exp_data_set.data_reference

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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)75,4424
Polymers74,3892
Non-polymers1,0532
Water6,684371
1
A: Mast/stem cell growth factor receptor Kit
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,7212
Polymers37,1941
Non-polymers5271
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)37,7212
Polymers37,1941
Non-polymers5271
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)59.220, 59.220, 192.600
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-9OO / (1~{S})-~{N}-ethyl-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: 526.611 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C28H31FN10 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 371 / 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: 1.95 Å3/Da / Density % sol: 36.8 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 6.6 mg/mL, 750 mM Na3-citrate, 100 mM Hepes, pH 6.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-2 / Wavelength: 0.8731 Å
DetectorType: DECTRIS PILATUS3 X 2M / Detector: PIXEL / Date: Apr 21, 2022
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.8731 Å / Relative weight: 1
ReflectionResolution: 1.77→48.15 Å / Num. obs: 67020 / % possible obs: 100 % / Redundancy: 11.6 % / Biso Wilson estimate: 27.9 Å2 / CC1/2: 0.999 / Rrim(I) all: 0.129 / Net I/σ(I): 17.03
Reflection shellResolution: 1.77→1.8 Å / Redundancy: 6.72 % / Mean I/σ(I) obs: 1.48 / Num. unique obs: 3268 / CC1/2: 0.613 / Rrim(I) all: 1.691 / % possible all: 99.5

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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: 1.77→43.53 Å / SU ML: 0.2412 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 22.0181
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2063 3350 5 %
Rwork0.1814 63654 -
obs0.1826 67004 99.94 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 33.95 Å2
Refinement stepCycle: LAST / Resolution: 1.77→43.53 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4629 0 78 371 5078
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00794946
X-RAY DIFFRACTIONf_angle_d0.94436738
X-RAY DIFFRACTIONf_chiral_restr0.0561727
X-RAY DIFFRACTIONf_plane_restr0.0083857
X-RAY DIFFRACTIONf_dihedral_angle_d14.04921781
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.77-1.80.40031380.3912634X-RAY DIFFRACTION99.32
1.8-1.820.31211350.3442563X-RAY DIFFRACTION100
1.82-1.850.35151410.29432678X-RAY DIFFRACTION99.89
1.85-1.880.35831340.25972533X-RAY DIFFRACTION99.93
1.88-1.910.27581400.22462669X-RAY DIFFRACTION99.96
1.91-1.950.26691380.20392630X-RAY DIFFRACTION99.96
1.95-1.990.22381370.20722592X-RAY DIFFRACTION100
1.99-2.030.21971370.20352602X-RAY DIFFRACTION99.93
2.03-2.070.26411380.21122640X-RAY DIFFRACTION99.93
2.07-2.120.24141390.21372639X-RAY DIFFRACTION100
2.12-2.170.20391370.17022613X-RAY DIFFRACTION100
2.17-2.230.22821380.17632613X-RAY DIFFRACTION99.93
2.23-2.30.19841400.17662658X-RAY DIFFRACTION100
2.3-2.370.22021400.17972666X-RAY DIFFRACTION100
2.37-2.450.21181390.17892628X-RAY DIFFRACTION100
2.45-2.550.26021380.1892623X-RAY DIFFRACTION100
2.55-2.670.22211390.19222639X-RAY DIFFRACTION99.96
2.67-2.810.21541410.19062687X-RAY DIFFRACTION100
2.81-2.990.22441400.19362661X-RAY DIFFRACTION100
2.99-3.220.19891400.18742665X-RAY DIFFRACTION99.96
3.22-3.540.18961420.17752692X-RAY DIFFRACTION100
3.54-4.050.16251420.1492700X-RAY DIFFRACTION100
4.05-5.10.14511440.13832741X-RAY DIFFRACTION100
5.1-43.530.19631530.17082888X-RAY DIFFRACTION99.87
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)
12.103468777980.769288734484-0.315020161650.9707958584380.2858554497081.59489277810.089121041653-0.341542251227-0.097659150840.212869580843-0.1332160819410.0215040494298-0.104256819066-0.08812530413070.04072055575040.2493103517510.005562495044350.01463519247610.2094454795150.01403700034410.185241813501-14.1047202211-3.337598314962.8626523791
21.302973967620.3713566441130.6048503756561.343339230560.487902988993.738400684070.0041732856862-0.106062539098-0.0177828338351-0.0424274493797-0.0138893817890.00621045911868-0.223257458638-0.2232061096230.01046513692250.1864787076640.0277361453170.002909770911060.1631405687420.008890550648350.179128004997-16.8670220132-5.2354200804447.6345809763
33.16972428634-0.5989122669750.6860227083911.978796728260.109407310852.759951450370.06377703430230.224481612842-0.107244897644-0.140302414308-0.03017943409470.0526621847341-0.1312272805990.073932192982-0.03397677288380.1835488196880.00628395228464-0.01414862517360.222685779077-0.01313585624730.1501392878-12.9053898543-12.097189288131.7757091869
41.145528059330.4312584115730.3655585263641.62994501602-0.3079114670181.68360163619-0.09928414075430.09621280668930.123639489756-0.118484904429-0.0621701003604-0.222402680966-0.1344338516110.05124538581440.1461453489380.2041089954950.0292432488535-0.02183962299360.2576612803260.01635685161370.2709238746767.17272834587-0.132884433663-12.0889383934
50.210579487946-0.430774981757-0.09607192276893.20117688995-1.093822512920.763566185743-0.218948151128-0.240856437540.4561804595630.118346733854-0.04310638509270.295608165879-0.523426523465-0.4948514664130.1489591019260.323836819130.121217321473-0.09226984221890.361225561684-0.08873970118430.3705955234983.670219594058.934405651798.38783607347
62.47015860278-0.36155386820.9372298186521.29232210701-0.1440716161372.72438471592-0.103341499836-0.2208239600840.08757194520520.06166500605180.009564787423190.0314883439416-0.0510862585648-0.333564029470.07517389490530.1753203342270.0249565879519-0.02216355636660.183681089056-0.01952006548670.18078441205913.0879300408-1.8449420810910.7805479274
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION

IDRefine TLS-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11chain 'A' and (resid 566 through 630 )AA566 - 6301 - 65
22chain 'A' and (resid 631 through 830 )AA631 - 83066 - 195
33chain 'A' and (resid 831 through 932 )AA831 - 932196 - 297
44chain 'B' and (resid 567 through 688 )BC567 - 6882 - 123
55chain 'B' and (resid 689 through 786 )BC689 - 786124 - 151
66chain 'B' and (resid 787 through 931 )BC787 - 931152 - 295

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