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- PDB-6joi: Crystal structure of PDGFRA T674I in complex with crenolanib by c... -

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Entry
Database: PDB / ID: 6joi
TitleCrystal structure of PDGFRA T674I in complex with crenolanib by co-crystallization
ComponentsPlatelet-derived growth factor receptor alpha
KeywordsONCOPROTEIN / PDGFRA / T674I / Inhibitor / crenolanib
Function / homology
Function and homology information


platelet-derived growth factor alpha-receptor activity / platelet-derived growth factor receptor-alpha signaling pathway / Imatinib-resistant PDGFR mutants / Sunitinib-resistant PDGFR mutants / Regorafenib-resistant PDGFR mutants / Sorafenib-resistant PDGFR mutants / PDGFR mutants bind TKIs / metanephric glomerular capillary formation / regulation of mesenchymal stem cell differentiation / luteinization ...platelet-derived growth factor alpha-receptor activity / platelet-derived growth factor receptor-alpha signaling pathway / Imatinib-resistant PDGFR mutants / Sunitinib-resistant PDGFR mutants / Regorafenib-resistant PDGFR mutants / Sorafenib-resistant PDGFR mutants / PDGFR mutants bind TKIs / 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 / embryonic skeletal system morphogenesis / vascular endothelial growth factor binding / retina vasculature development in camera-type eye / cardiac myofibril assembly / embryonic digestive tract morphogenesis / vascular endothelial growth factor receptor activity / Leydig cell differentiation / cell activation / male genitalia development / positive regulation of chemotaxis / Signaling by PDGF / signal transduction involved in regulation of gene expression / embryonic cranial skeleton morphogenesis / platelet-derived growth factor receptor binding / face morphogenesis / estrogen metabolic process / adrenal gland development / roof of mouth development / odontogenesis of dentin-containing tooth / 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 / positive regulation of calcium-mediated signaling / transmembrane receptor protein tyrosine kinase activity / Downstream signal transduction / extracellular matrix organization / cell chemotaxis / regulation of actin cytoskeleton organization / cellular response to amino acid stimulus / lung development / wound healing / receptor protein-tyrosine kinase / cilium / platelet aggregation / cellular response to reactive oxygen species / peptidyl-tyrosine phosphorylation / Constitutive Signaling by Aberrant PI3K in Cancer / positive regulation of fibroblast proliferation / cell junction / PIP3 activates AKT signaling / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / RAF/MAP kinase cascade / in utero embryonic development / protein autophosphorylation / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of ERK1 and ERK2 cascade / receptor complex / protein kinase activity / positive regulation of cell migration / external side of plasma membrane / positive regulation of cell population proliferation / protein-containing complex binding / endoplasmic reticulum membrane / Golgi apparatus / protein homodimerization activity / protein-containing complex / nucleoplasm / ATP binding / membrane / nucleus / plasma membrane / 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 / Tyrosine protein kinases specific active-site signature. ...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. / Immunoglobulin subtype / Immunoglobulin / Tyrosine-protein kinase, active site / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / 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-6T2 / Platelet-derived growth factor receptor alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.1 Å
AuthorsLiang, L. / Yan, X.E. / Yun, C.H.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China China
CitationJournal: To Be Published
Title: Crystal structure of PDGFRA T674I in complex with crenolanib by co-crystallization
Authors: Liang, L. / Yan, X.E.
History
DepositionMar 22, 2019Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Mar 25, 2020Provider: repository / Type: Initial release
Revision 1.1Nov 22, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Platelet-derived growth factor receptor alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,4742
Polymers43,0301
Non-polymers4441
Water28816
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area15490 Å2
Unit cell
Length a, b, c (Å)52.757, 73.992, 103.706
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Platelet-derived growth factor receptor alpha / PDGFR-alpha / Alpha platelet-derived growth factor receptor / Alpha-type platelet-derived growth ...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: 43030.336 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-6T2 / 1-(2-{5-[(3-Methyloxetan-3-yl)methoxy]-1H-benzimidazol-1-yl}quinolin-8-yl)piperidin-4-amine / Crenolanib


Mass: 443.541 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H29N5O2 / Comment: inhibitor*YM
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 16 / 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: 2.35 Å3/Da / Density % sol: 47.7 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / Details: 0.1M NaCl, 0.1M Tris pH 8.0, 15% PEG 4000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL19U1 / Wavelength: 0.97776 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: May 15, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97776 Å / Relative weight: 1
ReflectionResolution: 3.1→50 Å / Num. obs: 7841 / % possible obs: 98.65 % / Redundancy: 6.3 % / Rpim(I) all: 0.067 / Net I/σ(I): 13
Reflection shellResolution: 3.1→3.34 Å

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Processing

Software
NameVersionClassification
PHENIX(dev_2400: ???)refinement
DENZOdata reduction
HKL-3000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5K5X

5k5x


Resolution: 3.1→47.022 Å / SU ML: 0.4 / Cross valid method: FREE R-VALUE / σ(F): 1.37 / Phase error: 24.16
RfactorNum. reflection% reflection
Rfree0.2438 399 5.09 %
Rwork0.2225 --
obs0.2235 7841 98.65 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 3.1→47.022 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2361 0 33 16 2410
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0132460
X-RAY DIFFRACTIONf_angle_d1.5023333
X-RAY DIFFRACTIONf_dihedral_angle_d22.835920
X-RAY DIFFRACTIONf_chiral_restr0.093360
X-RAY DIFFRACTIONf_plane_restr0.008411
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.0777-3.52290.31451400.28822361X-RAY DIFFRACTION96
3.5229-4.4380.25091260.21042476X-RAY DIFFRACTION100
4.438-47.02770.20961330.20932605X-RAY DIFFRACTION100

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