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- PDB-8pqg: c-KIT T670I mutated kinase domain in complex with avapritinib -

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Basic information

Entry
Database: PDB / ID: 8pqg
Titlec-KIT T670I mutated 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 / gatekeeper mutant / gatekeeper mutation / 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-9JI / Mast/stem cell growth factor receptor Kit
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.4 Å
AuthorsTeuber, A. / 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 / Derived calculations / Structure summary
Category: chem_comp / entity ...chem_comp / entity / pdbx_entity_nonpoly / pdbx_related_exp_data_set
Item: _chem_comp.name / _chem_comp.pdbx_synonyms ..._chem_comp.name / _chem_comp.pdbx_synonyms / _entity.pdbx_description / _pdbx_entity_nonpoly.name / _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
C: Mast/stem cell growth factor receptor Kit
hetero molecules


Theoretical massNumber of molelcules
Total (without water)75,4104
Polymers74,4132
Non-polymers9972
Water75742
1
A: Mast/stem cell growth factor receptor Kit
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,7052
Polymers37,2061
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)37,7052
Polymers37,2061
Non-polymers4991
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)58.750, 59.090, 192.420
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: 37206.480 Da / Num. of mol.: 2 / Mutation: T670I
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 / Avapritinib / (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: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 42 / 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: 2.24 Å3/Da / Density % sol: 45.19 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 6 mg/mL, 25% PEG3350, 200 mM Na-citrate, 100 mM Bis-Tris-Propane, pH 6.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1 Å
DetectorType: DECTRIS EIGER2 X 16M / Detector: PIXEL / Date: Aug 29, 2022
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.4→48.11 Å / Num. obs: 27017 / % possible obs: 99.8 % / Redundancy: 10.92 % / Biso Wilson estimate: 59.09 Å2 / CC1/2: 0.999 / Rrim(I) all: 0.1 / Net I/σ(I): 14.36
Reflection shellResolution: 2.4→2.5 Å / Mean I/σ(I) obs: 1.21 / Num. unique obs: 3038 / CC1/2: 0.557 / Rrim(I) all: 1.709 / % 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: 2.4→48.1 Å / SU ML: 0.2932 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 27.9937
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2311 1351 5 %
Rwork0.2061 25664 -
obs0.2074 27015 99.84 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 67.59 Å2
Refinement stepCycle: LAST / Resolution: 2.4→48.1 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4590 0 74 42 4706
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00374821
X-RAY DIFFRACTIONf_angle_d0.58656564
X-RAY DIFFRACTIONf_chiral_restr0.0412712
X-RAY DIFFRACTIONf_plane_restr0.0046899
X-RAY DIFFRACTIONf_dihedral_angle_d11.25021779
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.4-2.490.38661320.33542504X-RAY DIFFRACTION99.47
2.49-2.590.34091330.32052531X-RAY DIFFRACTION99.44
2.59-2.70.3571320.31482507X-RAY DIFFRACTION99.85
2.7-2.850.28991330.27212524X-RAY DIFFRACTION100
2.85-3.020.3161320.27132526X-RAY DIFFRACTION99.81
3.02-3.260.28231360.26082573X-RAY DIFFRACTION100
3.26-3.580.28911340.21532557X-RAY DIFFRACTION100
3.58-4.10.20341360.17942580X-RAY DIFFRACTION99.93
4.1-5.170.16271380.16032614X-RAY DIFFRACTION99.96
5.17-48.10.19211450.17562748X-RAY DIFFRACTION99.97
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)
12.19023840762-0.1564912188220.4401132212362.269453103870.2323877432972.34875458222-0.104966192774-0.164144508735-0.1797780165410.105054858675-0.07255396268860.195353308287-0.0121065264622-0.2545300392050.1678806043910.4861704716960.04363565146950.02934424796680.377501563636-0.04226789706470.492116715711-15.6259310539-21.828830705758.7571974242
22.02641785725-1.25887777232-0.7023101886234.76825344791.564092700323.709616262460.06334638483130.05054498173590.144761011678-0.365260724795-0.2353362985580.318603598943-0.57420261318-0.172138669410.1399687757580.5196643317050.0352485960334-0.03594603727990.446105031272-0.02784421102940.458616789893-13.7419854644-26.600125828937.5368710454
31.706262484111.12720820548-0.2231897127982.95373570569-0.4459694127093.27971660833-0.09518738941380.213321990127-0.180880563403-0.5583650885980.0237306127474-0.1570340687870.190896328937-0.182864518139-0.01507245736750.4702921645980.00664953676019-4.32260685219E-50.528392302162-0.02910476054450.383638971445-13.1803908369-5.95409424468-13.6359683832
42.206138701581.01525950504-0.2305343215153.510207611050.4703867698275.33999930774-0.1362678641280.2307436030630.185171509693-0.3895386462-0.0434301983101-0.174457823183-0.426099990646-0.232888427745-0.06648933884510.681609329428-0.03951952781830.04319421747490.5950727283370.05980226195180.525512694124-8.582805637025.9100458711-16.0096296276
52.623219887170.7068251491920.3477132410343.696051498150.4024137896854.85104658010.08101708037160.00792980905232-0.118381022596-0.249962270089-0.02022135980330.09799211056510.00633082949699-0.257740199185-0.01956574794040.533885375829-0.00140039779373-0.03692360832760.5301303166750.03973706434170.520876837881-11.0596747804-1.23041138351-9.73385779498
62.372896685180.50831490605-0.2307874476133.423623976680.5043808951114.27297481820.126693077765-0.07161490606530.345751278708-0.0772631236925-0.1028361968790.224546785931-0.558247756351-0.228680283619-0.01492993767070.5005778563880.06287099242620.03861662978130.4880323890450.0222269679170.466326764619-9.395756818098.1071935087.5159395875
71.554163650911.734944274660.9888505335092.74308895861.406935313820.7864171597410.2415248321730.213176692471-0.591159276616-0.448564597083-0.4862277120770.03047799043150.9998744386950.530273007245-0.1017222119020.8692281272290.1038206230580.06546142570710.7960389923380.01032111819090.713236306131-5.90599177331-12.86624269080.337730333834
83.72185643794-1.262994625010.1973400008223.29003964498-0.1366826268252.86066558327-0.0718483727473-0.08308460477990.2019154294580.2435016280350.0549460432517-0.2502939384620.0469034282688-0.06498431080020.007417041201350.4370989638140.01794087735660.001286202193250.362185129246-0.02845795499560.3649425795970.337149401261-3.1724600710415.3150425136
94.95172882077-1.708579173570.7065295332055.178724265590.04520615462483.81813548202-0.219047246879-0.5264370574820.4788559546570.665666470299-0.2098153701550.566104996351-0.434139647805-0.7965432219910.1457397385620.599573691689-0.0123041876168-0.03373639288710.892502065915-0.02995925139690.755202754315-18.30272873533.4966510142618.6275498452
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 765 )AA566 - 7651 - 131
22chain 'A' and (resid 766 through 931 )AA766 - 931132 - 292
33chain 'C' and (resid 565 through 600 )CB565 - 6001 - 36
44chain 'C' and (resid 601 through 630 )CB601 - 63037 - 66
55chain 'C' and (resid 631 through 677 )CB631 - 67767 - 113
66chain 'C' and (resid 678 through 808 )CB678 - 808114 - 176
77chain 'C' and (resid 809 through 828 )CB809 - 828177 - 196
88chain 'C' and (resid 829 through 916 )CB829 - 916197 - 284
99chain 'C' and (resid 917 through 932 )CB917 - 932285 - 300

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