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- PDB-8pqh: PDGFRA T674I mutant kinase domain in complex with avapritinib -

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Basic information

Entry
Database: PDB / ID: 8pqh
TitlePDGFRA T674I mutant kinase domain in complex with avapritinib
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 / gatekeeper mutant / 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 / positive regulation of chemotaxis / male genitalia development / 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 / microvillus / platelet-derived growth factor receptor signaling pathway / odontogenesis of dentin-containing tooth / roof of mouth development / negative regulation of platelet activation / white fat cell differentiation / 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 / cytoplasm / cytosol
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
Chem-9JI / DI(HYDROXYETHYL)ETHER / Platelet-derived growth factor receptor alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.5 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
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: Platelet-derived growth factor receptor alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,8313
Polymers40,2261
Non-polymers6052
Water39622
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area260 Å2
ΔGint2 kcal/mol
Surface area16430 Å2
Unit cell
Length a, b, c (Å)52.270, 73.260, 102.590
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 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: 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.: 1 / Source method: obtained synthetically / Formula: C26H27FN10 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H10O3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 22 / 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: 2.02 Å3/Da / Density % sol: 39.24 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion, hanging drop / Details: 10 mg/mL, 13% PEG3350, 200 mM KCl

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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: Feb 17, 2021
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.5→46.75 Å / Num. obs: 14185 / % possible obs: 100 % / Redundancy: 13.09 % / Biso Wilson estimate: 71.45 Å2 / CC1/2: 0.999 / Rrim(I) all: 0.08 / Net I/σ(I): 18.79
Reflection shellResolution: 2.5→2.6 Å / Redundancy: 13.67 % / Mean I/σ(I) obs: 2.06 / Num. unique obs: 1529 / CC1/2: 0.77 / Rrim(I) all: 1.499 / % 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: 2.5→46.57 Å / SU ML: 0.399 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 30.9463
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2486 708 5 %
Rwork0.2184 13466 -
obs0.2201 14174 99.92 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 78.98 Å2
Refinement stepCycle: LAST / Resolution: 2.5→46.57 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2430 0 44 23 2497
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00872542
X-RAY DIFFRACTIONf_angle_d1.00373464
X-RAY DIFFRACTIONf_chiral_restr0.0568383
X-RAY DIFFRACTIONf_plane_restr0.0079465
X-RAY DIFFRACTIONf_dihedral_angle_d5.8385386
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.5-2.690.39671390.35432630X-RAY DIFFRACTION99.96
2.69-2.960.32271390.28682650X-RAY DIFFRACTION99.96
2.96-3.390.33271410.27892666X-RAY DIFFRACTION99.96
3.39-4.270.2511410.2092696X-RAY DIFFRACTION99.82
4.27-46.570.2021480.18592824X-RAY DIFFRACTION99.9
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)
14.876921502060.488164204663-3.75552697960.0970916852606-0.3334426846622.92564010205-0.1138405136980.3796843633870.286173731594-0.4386645233230.103760140526-0.154535622235-0.1922770182920.389798906934-0.2318681773261.128853425440.005106715522010.005932459000170.9149503611270.03459253485610.8632529694095.1744735207530.8746537418-6.72532974808
21.5199660859-0.370316258219-0.9968966150353.967905681560.2624162270835.74770014337-0.115166780059-0.107485504427-0.1653322674180.369839777791-0.109719951131-0.1224597899350.3771040433250.08906915665240.2172946325540.402125508495-0.00633388024912-0.02759146682770.4398248538740.0706611275220.4295726306714.970577485972.6011452328413.9254216447
36.430472096271.13850354243-3.520167253572.854436975830.4367224554815.28628293767-0.05360539195160.18604658706-0.0499314398804-0.0896016918586-0.03581175913830.2003977229280.287230510234-0.4989408346280.104895548990.537987743795-0.0147988477571-0.0662233473390.459045668003-0.008774605615230.4055756864045.392517451793.52069008446-7.74819345895
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 555 through 576 )555 - 5761 - 21
22chain 'A' and (resid 577 through 791 )577 - 79122 - 141
33chain 'A' and (resid 792 through 971 )792 - 971142 - 321

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