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- PDB-8pqk: APO crystal structure of PDGFRA-T674I kinase domain -

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Basic information

Entry
Database: PDB / ID: 8pqk
TitleAPO crystal structure of PDGFRA-T674I kinase domain
ComponentsPlatelet-derived growth factor receptor alpha
KeywordsTRANSFERASE / PDGFRA / protein kinase / tyrosine kinase / transmembrane receptor / platelet-derived growth factor / platelet-derived growth factor receptor / GIST / gastrointestinal stromal tumors / cancer / gatekeeper mutant / gatekeeper mutation / 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 / metanephric glomerular capillary formation / regulation of mesenchymal stem cell differentiation / luteinization ...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 / 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 / embryonic digestive tract morphogenesis / Leydig cell differentiation / cardiac myofibril assembly / Signaling by PDGF / cell activation / male genitalia development / positive regulation of chemotaxis / phospholipase C activator activity / embryonic cranial skeleton morphogenesis / platelet-derived growth factor receptor binding / signal transduction involved in regulation of gene expression / face morphogenesis / estrogen metabolic process / adrenal gland development / odontogenesis of dentin-containing tooth / roof of mouth development / microvillus / platelet-derived growth factor receptor signaling pathway / 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 / transmembrane receptor protein tyrosine kinase activity / extracellular matrix organization / Downstream signal transduction / positive regulation of calcium-mediated signaling / cell surface receptor protein tyrosine kinase signaling pathway / cell chemotaxis / cellular response to reactive oxygen species / regulation of actin cytoskeleton organization / cellular response to amino acid stimulus / lung development / wound healing / placental growth factor receptor activity / insulin receptor activity / vascular endothelial growth factor receptor activity / hepatocyte growth factor receptor activity / macrophage colony-stimulating factor receptor activity / platelet-derived growth factor alpha-receptor activity / platelet-derived growth factor beta-receptor activity / stem cell factor receptor activity / boss receptor activity / protein tyrosine kinase collagen receptor activity / brain-derived neurotrophic factor receptor activity / transmembrane-ephrin receptor activity / GPI-linked ephrin receptor activity / epidermal growth factor receptor activity / fibroblast growth factor receptor activity / insulin-like growth factor receptor activity / receptor protein-tyrosine kinase / peptidyl-tyrosine phosphorylation / platelet aggregation / positive regulation of fibroblast proliferation / Constitutive Signaling by Aberrant PI3K in Cancer / cell junction / cell migration / PIP3 activates AKT signaling / RAF/MAP kinase cascade / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / protein autophosphorylation / in utero embryonic development / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor complex / positive regulation of ERK1 and ERK2 cascade / 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 / 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 ...Platelet-derived growth factor receptor alpha / 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. / Tyrosine-protein kinase, active site / Immunoglobulin subtype / Immunoglobulin / 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: 2 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

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Assembly

Deposited unit
A: Platelet-derived growth factor receptor alpha


Theoretical massNumber of molelcules
Total (without water)40,2261
Polymers40,2261
Non-polymers00
Water2,486138
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 area14600 Å2
MethodPISA
Unit cell
Length a, b, c (Å)95.900, 49.020, 76.980
Angle α, β, γ (deg.)90.000, 100.690, 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

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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: 40226.371 Da / Num. of mol.: 1 / Mutation: T674I
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.: 138 / 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: 2.41 Å3/Da / Density % sol: 49 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 10 mg/mL, 22% 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: 1.00003 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: 1.00003 Å / Relative weight: 1
ReflectionResolution: 2→47.12 Å / Num. obs: 23810 / % possible obs: 99.3 % / Redundancy: 6.82 % / Biso Wilson estimate: 33.17 Å2 / CC1/2: 0.997 / Rrim(I) all: 0.129 / Net I/σ(I): 9.24
Reflection shellResolution: 2→2.1 Å / Redundancy: 6.69 % / Mean I/σ(I) obs: 2.04 / Num. unique obs: 3145 / CC1/2: 0.782 / Rrim(I) all: 0.851 / % possible all: 98.1

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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→43.81 Å / SU ML: 0.2598 / Cross valid method: FREE R-VALUE / σ(F): 1.37 / Phase error: 24.7369
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2219 1191 5 %
Rwork0.196 22606 -
obs0.1974 23797 99.25 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 37.56 Å2
Refinement stepCycle: LAST / Resolution: 2→43.81 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2558 0 0 138 2696
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00232647
X-RAY DIFFRACTIONf_angle_d0.47293592
X-RAY DIFFRACTIONf_chiral_restr0.0417398
X-RAY DIFFRACTIONf_plane_restr0.0034448
X-RAY DIFFRACTIONf_dihedral_angle_d12.0784973
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2-2.080.35731290.30952443X-RAY DIFFRACTION97.68
2.08-2.170.23381310.24292488X-RAY DIFFRACTION98.9
2.18-2.290.25451300.22042470X-RAY DIFFRACTION99.12
2.29-2.430.26121320.22932516X-RAY DIFFRACTION99.36
2.43-2.620.30111310.23552484X-RAY DIFFRACTION99.2
2.62-2.880.24061330.21812528X-RAY DIFFRACTION99.55
2.88-3.30.24491330.20912514X-RAY DIFFRACTION99.7
3.3-4.160.18121340.16362561X-RAY DIFFRACTION99.89
4.16-43.810.18661380.16422602X-RAY DIFFRACTION99.82
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)
10.591512633996-0.121103261936-0.08071700857210.1160641050470.0181940069305-0.0556504542360.0623681592772-0.007577218783850.0724040189890.0255758104957-0.176206160026-0.258528474691-0.005915397192750.131160750128-0.0001323465248440.3426919676030.0198685348365-0.03629259823420.3247012545440.02960102247880.34722832308734.74005323294.1579724327229.792264234
20.0391874098696-0.237331643820.06254840845980.659455873335-0.2740625914550.914485303129-0.07062299643690.0700468582172-0.06222079934190.0045939707477-0.007796890191030.0367209297270.08205885108720.0160761271351-2.5542065534E-50.2268030273230.001560011311710.01466615991080.25930534513-0.007210248950470.27711093606130.4816105419-3.7748669807725.8166299136
30.3000717341080.048256051927-0.09025627195430.202501135223-0.9114532328211.08070811670.0525703750950.0861468852358-0.103778250654-0.0150558028154-0.02595895639980.1170034883040.140975932141-0.0793084322386-6.93726313743E-50.2882670457490.0187141891006-0.01483791628430.274682974331-0.03279467963410.30240192582617.67349427251.0704540466120.6587284397
40.329686390544-0.3881608762130.07469731403171.50194933035-0.07466518453990.8483374395220.0746642162375-0.04244107498780.0689822475379-0.11361187253-0.0610301902575-0.137561584569-0.04651105079080.06126373988153.17577712134E-50.2451630841460.02402059841960.009554500941570.2558673400030.003632971929610.25578359023524.529025238912.759089279513.4711245787
50.01551391387790.1671850305770.01234519890510.1185241876490.02512952007150.210056256124-0.06541265849830.0151923366992-0.307960464914-0.454248010304-0.0596796295969-0.107797414847-0.22111230284-0.129353580268-6.68803493727E-50.4871679245240.06306307582050.03801480648620.3331299620770.01444051242410.30081023683722.500408647621.52990802321.23829093968
60.2722046979010.08442341155780.1868857189050.6254941788830.3899615958630.7084435745740.0125066229822-0.1089080180580.1456622706840.07781397615640.05614428422740.135288531222-0.326763533036-0.1530999290152.61236407512E-50.2844329428610.05381432002540.02634061407670.309112394950.008727293562840.31194621702512.904095139719.410268048921.0847841722
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 554 through 595 )554 - 5951 - 33
22chain 'A' and (resid 596 through 651 )596 - 65134 - 89
33chain 'A' and (resid 652 through 791 )652 - 79190 - 140
44chain 'A' and (resid 792 through 902 )792 - 902141 - 251
55chain 'A' and (resid 903 through 922 )903 - 922252 - 271
66chain 'A' and (resid 923 through 973 )923 - 973272 - 322

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