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- PDB-8pqj: PDGFRA wild-type kinase domain -

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Basic information

Entry
Database: PDB / ID: 8pqj
TitlePDGFRA wild-type kinase domain
ComponentsPlatelet-derived growth factor receptor alpha
KeywordsTRANSFERASE / PDGFRA protein kinase / avapritinib / inhibitor / tyrosine kinase / transmembrane receptor / platelet-derived growth factor receptor alpha / PDGF / platelet-derived growth factor / GIST / gastrointestinal stromal tumors / P16234
Function / homology
Function and homology information


Imatinib-resistant PDGFR mutants / Sunitinib-resistant PDGFR mutants / Regorafenib-resistant PDGFR mutants / Sorafenib-resistant PDGFR mutants / PDGFR mutants bind TKIs / platelet-derived growth factor receptor-alpha signaling pathway / platelet-derived growth factor receptor-ligand complex / platelet-derived growth factor alpha-receptor activity / metanephric glomerular capillary formation / regulation of mesenchymal stem cell differentiation ...Imatinib-resistant PDGFR mutants / Sunitinib-resistant PDGFR mutants / Regorafenib-resistant PDGFR mutants / Sorafenib-resistant PDGFR mutants / PDGFR mutants bind TKIs / platelet-derived growth factor receptor-alpha signaling pathway / platelet-derived growth factor receptor-ligand complex / platelet-derived growth factor alpha-receptor activity / metanephric glomerular capillary formation / regulation of mesenchymal stem cell differentiation / luteinization / positive regulation of cell proliferation by VEGF-activated platelet derived growth factor receptor signaling pathway / platelet-derived growth factor binding / vascular endothelial growth factor binding / embryonic skeletal system morphogenesis / retina vasculature development in camera-type eye / vascular endothelial growth factor receptor activity / embryonic digestive tract morphogenesis / cardiac myofibril assembly / Leydig cell differentiation / cell activation / Signaling by PDGF / male genitalia development / positive regulation of chemotaxis / embryonic cranial skeleton morphogenesis / phospholipase C activator activity / platelet-derived growth factor receptor binding / estrogen metabolic process / face morphogenesis / signal transduction involved in regulation of gene expression / adrenal gland development / platelet-derived growth factor receptor signaling pathway / microvillus / odontogenesis of dentin-containing tooth / roof of mouth development / white fat cell differentiation / negative regulation of platelet activation / hematopoietic progenitor cell differentiation / Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants / Signaling by PDGFRA extracellular domain mutants / extracellular matrix organization / transmembrane receptor protein tyrosine kinase activity / Downstream signal transduction / positive regulation of calcium-mediated signaling / lung development / cell surface receptor protein tyrosine kinase signaling pathway / peptidyl-tyrosine phosphorylation / cellular response to reactive oxygen species / cell chemotaxis / regulation of actin cytoskeleton organization / cellular response to amino acid stimulus / wound healing / receptor protein-tyrosine kinase / platelet aggregation / positive regulation of fibroblast proliferation / Constitutive Signaling by Aberrant PI3K in Cancer / cell junction / cell migration / PIP3 activates AKT signaling / protein autophosphorylation / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / RAF/MAP kinase cascade / in utero embryonic development / positive regulation of ERK1 and ERK2 cascade / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor complex / protein kinase activity / nuclear body / cilium / positive regulation of cell migration / external side of plasma membrane / positive regulation of cell population proliferation / endoplasmic reticulum membrane / protein-containing complex binding / Golgi apparatus / protein homodimerization activity / protein-containing complex / nucleoplasm / ATP binding / nucleus / membrane / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Platelet-derived growth factor receptor alpha / Platelet-derived growth factor receptor Ig-like domain 4 / Tyrosine-protein kinase, receptor class III, conserved site / Receptor tyrosine kinase class III signature. / Immunoglobulin I-set / Immunoglobulin I-set domain / : / Immunoglobulin subtype 2 / Immunoglobulin C-2 Type / Tyrosine-protein kinase, catalytic domain ...Platelet-derived growth factor receptor alpha / Platelet-derived growth factor receptor Ig-like domain 4 / Tyrosine-protein kinase, receptor class III, conserved site / Receptor tyrosine kinase class III signature. / Immunoglobulin I-set / Immunoglobulin I-set 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 / Serine/Threonine protein kinases, catalytic domain / 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
Platelet-derived growth factor receptor alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.82 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 / 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: Platelet-derived growth factor receptor alpha


Theoretical massNumber of molelcules
Total (without water)40,2141
Polymers40,2141
Non-polymers00
Water3,675204
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area15340 Å2
MethodPISA
Unit cell
Length a, b, c (Å)96.380, 49.180, 77.040
Angle α, β, γ (deg.)90.000, 100.780, 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
Components on special symmetry positions
IDModelComponents
11A-1159-

HOH

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Components

#1: Protein Platelet-derived growth factor receptor alpha / PDGF-R-alpha / PDGFR-alpha / Alpha platelet-derived growth factor receptor / Alpha-type platelet- ...PDGF-R-alpha / PDGFR-alpha / Alpha platelet-derived growth factor receptor / Alpha-type platelet-derived growth factor receptor / CD140 antigen-like family member A / CD140a antigen / Platelet-derived growth factor alpha receptor / Platelet-derived growth factor receptor 2 / PDGFR-2


Mass: 40214.320 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PDGFRA, PDGFR2, RHEPDGFRA / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P16234, receptor protein-tyrosine kinase
#2: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 204 / Source method: isolated from a natural source / Formula: H2O

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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: 1.85 Å3/Da / Density % sol: 33.47 %
Crystal growTemperature: 285.15 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 10 mg/mL, 15% PEG3350, 100 mM Bis-Tris-Propane, pH 7.5

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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: Feb 14, 2022
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9998 Å / Relative weight: 1
ReflectionResolution: 1.82→47.34 Å / Num. obs: 32011 / % possible obs: 99.9 % / Redundancy: 6.84 % / Biso Wilson estimate: 33.9 Å2 / CC1/2: 0.999 / Rrim(I) all: 0.087 / Net I/σ(I): 12.45
Reflection shellResolution: 1.82→1.9 Å / Redundancy: 6.52 % / Mean I/σ(I) obs: 1.21 / Num. unique obs: 3827 / CC1/2: 0.461 / Rrim(I) all: 1.713 / % possible all: 100

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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: 1.82→37.84 Å / SU ML: 0.27 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 24.101
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2151 1599 5 %
Rwork0.1838 30399 -
obs0.1854 31998 99.89 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 40.3 Å2
Refinement stepCycle: LAST / Resolution: 1.82→37.84 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2608 0 0 204 2812
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00532702
X-RAY DIFFRACTIONf_angle_d0.77623666
X-RAY DIFFRACTIONf_chiral_restr0.0531405
X-RAY DIFFRACTIONf_plane_restr0.0062458
X-RAY DIFFRACTIONf_dihedral_angle_d5.0395368
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.82-1.880.45811450.44022753X-RAY DIFFRACTION99.86
1.88-1.950.31171430.28132742X-RAY DIFFRACTION99.9
1.95-2.020.2681440.2382736X-RAY DIFFRACTION99.97
2.02-2.120.25631440.22242730X-RAY DIFFRACTION99.97
2.12-2.230.22661460.18172765X-RAY DIFFRACTION100
2.23-2.370.21021440.18152745X-RAY DIFFRACTION100
2.37-2.550.26311460.20162765X-RAY DIFFRACTION99.97
2.55-2.810.23481450.2132754X-RAY DIFFRACTION99.9
2.81-3.210.24681460.1962784X-RAY DIFFRACTION99.97
3.21-4.050.18781460.15982775X-RAY DIFFRACTION99.62
4.05-37.840.17041500.14962850X-RAY DIFFRACTION99.7
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)
12.672220113441.533002477531.329631657494.227120313910.2311532937744.81810337641-0.1297166642020.2509394524280.615693736706-0.151509608247-0.0243273112452-0.863479253341-0.2304318712720.7793375427820.0398592552540.354459427619-0.00676577789507-0.04914039972880.3836833322060.04892155895510.56100448903438.051487026613.610646288524.9328984826
23.233463150792.84862019347-0.1929719536683.42026476722-0.1285768542362.960476644990.111224947804-0.244518607999-0.1790087893030.287190679809-0.217740655869-0.1766161317350.1053140926830.08643704186930.04624117498220.2423665821350.107581565258-0.02600180414360.2146509976180.004336119231970.29351684209231.0399547351-5.5324848860929.0164730349
32.422752938070.830976753103-1.145986794462.66011282213-0.1215495805473.97471960408-0.07584567501140.07656544977410.05266100412830.07322198643470.1229654017690.1141696288020.182537599428-0.1457290640550.09892523800490.235004835820.0323930033988-0.01573742798970.1881878917950.02540683823910.26216770558527.1020567744-7.590473951927.1198499179
45.93670696871-2.52277057059-3.855771612395.190662762972.54204035046.313583883730.161510686807-0.416351852333-0.197678835065-0.13136181517-0.00976793262163-0.297946912946-0.1315616992170.369935321576-0.06974299010820.281132674866-0.00187669262965-0.06240141295630.316545845390.01683169596930.29328899674636.91864584554.3805581556528.3703836635
51.10315763101-0.643858402625-0.1587719351652.02603844539-0.3873715914721.994096069110.07770895900580.0487906175619-0.00970335717451-0.136224854823-0.0814967501780.04121478322-0.0191349967984-0.02306260487550.002947198157220.2228291041760.016178790351-0.02891866541020.222907717419-0.01611209061640.2323951706822.0675220558.9012971116916.8341681507
64.940093328583.28221055547-5.018615144234.4777108982-2.83580365855.260313836140.06990485071940.253744534765-0.0455032024224-0.538741927754-0.0960152350103-0.102697761426-0.16480258096-0.2228200518330.009557590462190.5361303759140.070799360181-0.03610060797780.32236517417-0.0006533406748270.24883954962922.820065179918.80661312840.856291746138
72.507095548421.9575513916-2.082307583034.43334244283-2.942561983414.931638356350.0997374251694-0.04480174287220.2550113904590.06410588821070.07674456541510.377558526595-0.275319698007-0.262241303333-0.1955764360340.2438415787670.0680812226917-0.01199952756270.232387679406-0.0340792003370.26163897910712.852089510619.679561885621.2288623343
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 553 through 579 )553 - 5791 - 21
22chain 'A' and (resid 580 through 604 )580 - 60422 - 46
33chain 'A' and (resid 605 through 634 )605 - 63447 - 76
44chain 'A' and (resid 635 through 651 )635 - 65177 - 93
55chain 'A' and (resid 652 through 889 )652 - 88994 - 245
66chain 'A' and (resid 890 through 922 )890 - 922246 - 278
77chain 'A' and (resid 923 through 973 )923 - 973279 - 329

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