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- PDB-9kl4: Crystal structure of EGFR complexed with N-[4-[4-amino-6-ethynyl-... -

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Basic information

Entry
Database: PDB / ID: 9kl4
TitleCrystal structure of EGFR complexed with N-[4-[4-amino-6-ethynyl-5-(3-quinolyl)pyrrolo[2,3-d]pyrimidin-7-yl]norbornan-1-yl]pyrimidine-5-carboxamide
ComponentsEpidermal growth factor receptor
KeywordsTRANSFERASE / TKI
Function / homology
Function and homology information


multivesicular body, internal vesicle lumen / negative regulation of cardiocyte differentiation / Shc-EGFR complex / positive regulation of protein kinase C signaling / Inhibition of Signaling by Overexpressed EGFR / epidermal growth factor receptor activity / EGFR interacts with phospholipase C-gamma / regulation of peptidyl-tyrosine phosphorylation / epidermal growth factor binding / response to UV-A ...multivesicular body, internal vesicle lumen / negative regulation of cardiocyte differentiation / Shc-EGFR complex / positive regulation of protein kinase C signaling / Inhibition of Signaling by Overexpressed EGFR / epidermal growth factor receptor activity / EGFR interacts with phospholipase C-gamma / regulation of peptidyl-tyrosine phosphorylation / epidermal growth factor binding / response to UV-A / PLCG1 events in ERBB2 signaling / ERBB2-EGFR signaling pathway / morphogenesis of an epithelial fold / PTK6 promotes HIF1A stabilization / ERBB2 Activates PTK6 Signaling / digestive tract morphogenesis / Signaling by EGFR / intracellular vesicle / negative regulation of epidermal growth factor receptor signaling pathway / eyelid development in camera-type eye / cerebral cortex cell migration / protein insertion into membrane / ERBB2 Regulates Cell Motility / protein tyrosine kinase activator activity / Respiratory syncytial virus (RSV) attachment and entry / Signaling by ERBB4 / PI3K events in ERBB2 signaling / positive regulation of phosphorylation / positive regulation of peptidyl-serine phosphorylation / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / hair follicle development / MAP kinase kinase kinase activity / GAB1 signalosome / positive regulation of G1/S transition of mitotic cell cycle / embryonic placenta development / salivary gland morphogenesis / Signaling by ERBB2 / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / EGFR Transactivation by Gastrin / transmembrane receptor protein tyrosine kinase activity / GRB2 events in ERBB2 signaling / SHC1 events in ERBB2 signaling / ossification / NOTCH3 Activation and Transmission of Signal to the Nucleus / positive regulation of DNA repair / basal plasma membrane / cellular response to epidermal growth factor stimulus / EGFR downregulation / positive regulation of DNA replication / epithelial cell proliferation / positive regulation of epithelial cell proliferation / Signal transduction by L1 / positive regulation of protein localization to plasma membrane / cellular response to amino acid stimulus / phosphatidylinositol 3-kinase/protein kinase B signal transduction / cellular response to estradiol stimulus / clathrin-coated endocytic vesicle membrane / Signaling by ERBB2 TMD/JMD mutants / Constitutive Signaling by EGFRvIII / Downregulation of ERBB2 signaling / cell-cell adhesion / Signaling by ERBB2 ECD mutants / receptor protein-tyrosine kinase / Signaling by ERBB2 KD Mutants / negative regulation of protein catabolic process / positive regulation of miRNA transcription / kinase binding / ruffle membrane / epidermal growth factor receptor signaling pathway / positive regulation of protein phosphorylation / cell morphogenesis / neuron differentiation / positive regulation of fibroblast proliferation / HCMV Early Events / Constitutive Signaling by Aberrant PI3K in Cancer / actin filament binding / Cargo recognition for clathrin-mediated endocytosis / cell junction / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / transmembrane signaling receptor activity / positive regulation of canonical Wnt signaling pathway / Clathrin-mediated endocytosis / PIP3 activates AKT signaling / ATPase binding / virus receptor activity / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / RAF/MAP kinase cascade / positive regulation of cell growth / double-stranded DNA binding / protein tyrosine kinase activity / early endosome membrane / protein phosphatase binding / nuclear membrane / basolateral plasma membrane / learning or memory / Extra-nuclear estrogen signaling / cell surface receptor signaling pathway / endosome membrane
Similarity search - Function
: / Epidermal growth factor receptor transmembrane-juxtamembrane segment / Tyrosine protein kinase, EGF/ERB/XmrK receptor / Growth factor receptor domain 4 / Growth factor receptor domain IV / Receptor L-domain / Furin-like cysteine-rich domain / Receptor L-domain superfamily / Furin-like cysteine rich region / Receptor L domain ...: / Epidermal growth factor receptor transmembrane-juxtamembrane segment / Tyrosine protein kinase, EGF/ERB/XmrK receptor / Growth factor receptor domain 4 / Growth factor receptor domain IV / Receptor L-domain / Furin-like cysteine-rich domain / Receptor L-domain superfamily / Furin-like cysteine rich region / Receptor L domain / Furin-like repeat / Furin-like repeats / Growth factor receptor cysteine-rich domain superfamily / : / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / Tyrosine-protein kinase, active site / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
: / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.32 Å
AuthorsSuzuki, T. / Kasuga, H. / Yamamoto, F.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Res Sq / Year: 2025
Title: Discovery of TAS3351, a brain-penetrable 4th generation EGFR-TKI overcoming T790M and C797S resistant mutations.
Authors: Kasuga, H. / Kataoka, Y. / Yamamoto, F. / Tsuji, S. / Miyamoto, R. / Suzuki, T. / Mizuarai, S.
History
DepositionNov 14, 2024Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Sep 24, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,1153
Polymers37,5791
Non-polymers5362
Water97354
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area160 Å2
ΔGint-9 kcal/mol
Surface area16810 Å2
MethodPISA
Unit cell
Length a, b, c (Å)146.920, 146.920, 146.920
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number197
Space group name H-MI23

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Components

#1: Protein Epidermal growth factor receptor / Proto-oncogene c-ErbB-1 / Receptor tyrosine-protein kinase erbB-1


Mass: 37579.457 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EGFR, ERBB, ERBB1, HER1 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P00533, receptor protein-tyrosine kinase
#2: Chemical ChemComp-A1L53 / N-[4-[4-amino-6-ethynyl-5-(3-quinolyl)pyrrolo[2,3-d]pyrimidin-7-yl]norbornan-1-yl]pyrimidine-5-carboxamide / ~{N}-[4-(4-azanyl-6-ethynyl-5-quinolin-3-yl-pyrrolo[2,3-d]pyrimidin-7-yl)-1-bicyclo[2.2.1]heptanyl]pyrimidine-5-carboxamide


Mass: 500.554 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H24N8O / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 54 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationN

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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: 3.52 Å3/Da / Density % sol: 65.02 %
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 7 / Details: 1.2 M K/Na-tartrate, 0.1 M HEPES pH 7.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.99981 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Jul 9, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99981 Å / Relative weight: 1
ReflectionResolution: 2.32→103.89 Å / Num. obs: 22851 / % possible obs: 100 % / Redundancy: 24.7 % / CC1/2: 1 / Net I/σ(I): 21.8
Reflection shellResolution: 2.32→2.37 Å / Num. unique obs: 1163 / CC1/2: 0.607 / % possible all: 100

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Processing

Software
NameVersionClassification
autoPROCdata reduction
XDS(VERSION Jan 26data reduction
autoPROC(Version 1.1.7)data scaling
Aimlessdata scaling
REFMAC5.8.0155refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: Analysis by outsourcing.

Resolution: 2.32→103.89 Å / Cor.coef. Fo:Fc: 0.962 / Cor.coef. Fo:Fc free: 0.944 / SU B: 6.837 / SU ML: 0.156 / Cross valid method: THROUGHOUT / ESU R: 0.208 / ESU R Free: 0.194 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.23801 1296 5.7 %RANDOM
Rwork0.18565 ---
obs0.18863 21538 100 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 79.282 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å20 Å20 Å2
2--0 Å20 Å2
3---0 Å2
Refinement stepCycle: LAST / Resolution: 2.32→103.89 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2504 0 39 54 2597
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0192545
X-RAY DIFFRACTIONr_bond_other_d0.0040.022456
X-RAY DIFFRACTIONr_angle_refined_deg1.5841.9943461
X-RAY DIFFRACTIONr_angle_other_deg1.24235646
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.6655311
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.66824.095105
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.10615.09446
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.6991514
X-RAY DIFFRACTIONr_chiral_restr0.0890.2387
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0212824
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02545
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it12.91910.6391250
X-RAY DIFFRACTIONr_mcbond_other12.90710.6351249
X-RAY DIFFRACTIONr_mcangle_it16.48317.8861559
X-RAY DIFFRACTIONr_mcangle_other16.48617.8941560
X-RAY DIFFRACTIONr_scbond_it14.22311.071295
X-RAY DIFFRACTIONr_scbond_other14.21711.0791296
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other18.56218.1881903
X-RAY DIFFRACTIONr_long_range_B_refined21.10489.4722705
X-RAY DIFFRACTIONr_long_range_B_other21.10689.4682705
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.325→2.385 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.394 95 -
Rwork0.311 1564 -
obs--100 %

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