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- PDB-9df3: EGFR Exon20 insertion mutant SVD bound with (S)-3-((3-chloro-2-me... -

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Basic information

Entry
Database: PDB / ID: 9df3
TitleEGFR Exon20 insertion mutant SVD bound with (S)-3-((3-chloro-2-methoxyphenyl)amino)-2-(3-((tetrahydrofuran-2-yl)methoxy)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one
ComponentsEpidermal growth factor receptor
KeywordsONCOPROTEIN / TRANSFERASE/TRANSFERASE INHIBITOR / Kinase / Inhibitor / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


positive regulation of protein kinase C activity / multivesicular body, internal vesicle lumen / positive regulation of prolactin secretion / negative regulation of cardiocyte differentiation / response to hydroxyisoflavone / diterpenoid metabolic process / Shc-EGFR complex / Inhibition of Signaling by Overexpressed EGFR / ovulation cycle / EGFR interacts with phospholipase C-gamma ...positive regulation of protein kinase C activity / multivesicular body, internal vesicle lumen / positive regulation of prolactin secretion / negative regulation of cardiocyte differentiation / response to hydroxyisoflavone / diterpenoid metabolic process / Shc-EGFR complex / Inhibition of Signaling by Overexpressed EGFR / ovulation cycle / EGFR interacts with phospholipase C-gamma / positive regulation of mucus secretion / epidermal growth factor binding / regulation of peptidyl-tyrosine phosphorylation / response to UV-A / tongue development / PLCG1 events in ERBB2 signaling / midgut development / ERBB2-EGFR signaling pathway / digestive tract morphogenesis / hydrogen peroxide metabolic process / morphogenesis of an epithelial fold / PTK6 promotes HIF1A stabilization / ERBB2 Activates PTK6 Signaling / Signaling by EGFR / intracellular vesicle / response to cobalamin / 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 / Signaling by ERBB4 / Respiratory syncytial virus (RSV) attachment and entry / PI3K events in ERBB2 signaling / negative regulation of mitotic cell cycle / MAP kinase kinase kinase activity / hair follicle development / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / positive regulation of G1/S transition of mitotic cell cycle / GAB1 signalosome / positive regulation of bone resorption / embryonic placenta development / positive regulation of phosphorylation / salivary gland morphogenesis / peptidyl-tyrosine autophosphorylation / positive regulation of peptidyl-serine phosphorylation / positive regulation of glial cell proliferation / positive regulation of vasoconstriction / Signaling by ERBB2 / transmembrane receptor protein tyrosine kinase activity / GRB2 events in EGFR signaling / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / GRB2 events in ERBB2 signaling / SHC1 events in ERBB2 signaling / cellular response to epidermal growth factor stimulus / cellular response to dexamethasone stimulus / positive regulation of synaptic transmission, glutamatergic / ossification / positive regulation of DNA repair / neuron projection morphogenesis / positive regulation of superoxide anion generation / positive regulation of epithelial cell proliferation / liver regeneration / epithelial cell proliferation / basal plasma membrane / Signal transduction by L1 / positive regulation of DNA replication / positive regulation of protein localization to plasma membrane / astrocyte activation / phosphatidylinositol 3-kinase/protein kinase B signal transduction / NOTCH3 Activation and Transmission of Signal to the Nucleus / cellular response to amino acid stimulus / positive regulation of smooth muscle cell proliferation / cellular response to estradiol stimulus / lung development / EGFR downregulation / synaptic membrane / Signaling by ERBB2 TMD/JMD mutants / clathrin-coated endocytic vesicle membrane / placental growth factor receptor activity / insulin receptor activity / vascular endothelial growth factor receptor activity / Constitutive Signaling by EGFRvIII / 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 / Signaling by ERBB2 ECD mutants
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: 1.68 Å
AuthorsHilbert, B.J. / Brooijmans, N. / Pagliarini, R.A. / Milgram, B.C.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Clin.Cancer Res. / Year: 2025
Title: STX-721, a Covalent EGFR/HER2 Exon 20 Inhibitor, Utilizes Exon 20-Mutant Dynamic Protein States and Achieves Unique Mutant Selectivity Across Human Cancer Models.
Authors: Pagliarini, R.A. / Henderson, J.A. / Milgram, B.C. / Borrelli, D.R. / Brooijmans, N. / Hilbert, B.J. / Huff, M.R. / Ito, T. / Kryukov, G.V. / Ladd, B. / Martin, B.R. / Motiwala, H. / ...Authors: Pagliarini, R.A. / Henderson, J.A. / Milgram, B.C. / Borrelli, D.R. / Brooijmans, N. / Hilbert, B.J. / Huff, M.R. / Ito, T. / Kryukov, G.V. / Ladd, B. / Martin, B.R. / Motiwala, H. / O'Hearn, E. / Tsai, C.F. / Wang, W. / Bellier, J. / Boland, L. / Clark, S. / Hensley, E. / Hata, A.N. / Kuzmic, P. / Guzman-Perez, A. / Jackson, E.L. / Stuart, D.D.
History
DepositionAug 29, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 14, 2025Provider: repository / Type: Initial release
Revision 1.1Jun 11, 2025Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year

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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)39,01010
Polymers37,8651
Non-polymers1,1469
Water3,801211
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: Protein contains mutation identified to block dimerization
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)40.060, 107.240, 175.290
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number20
Space group name H-MC2221
Components on special symmetry positions
IDModelComponents
11A-1381-

HOH

21A-1388-

HOH

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Components

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


Mass: 37864.672 Da / Num. of mol.: 1 / Mutation: V951R
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EGFR, ERBB, ERBB1, HER1 / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P00533, receptor protein-tyrosine kinase
#2: Chemical ChemComp-A1IMS / 3-[(3-chloranyl-2-methoxy-phenyl)amino]-2-[3-[[(2S)-oxolan-2-yl]methoxy]pyridin-4-yl]-1,5,6,7-tetrahydropyrrolo[3,2-c]pyridin-4-one


Mass: 468.933 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H25ClN4O4 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6O2
#4: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C3H8O3
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 211 / 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: 2.49 Å3/Da / Density % sol: 50.52 %
Crystal growTemperature: 291 K / Method: vapor diffusion
Details: 0.8 microliters 7.7 mg/mL protein mixed 1:1 with 100mM MES pH 6.2, 600 mM NaCl, 14% w/v PEG 4000. 0.2 microliters of 100 mM spermidine added to drop

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: NSRRC / Beamline: TPS 05A / Wavelength: 0.99984 Å
DetectorType: RAYONIX MX-300 / Detector: CCD / Date: Jun 11, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99984 Å / Relative weight: 1
ReflectionResolution: 1.68→45.78 Å / Num. obs: 43682 / % possible obs: 100 % / Redundancy: 14.4 % / CC1/2: 0.999 / Rmerge(I) obs: 0.083 / Rpim(I) all: 0.033 / Rrim(I) all: 0.089 / Net I/σ(I): 19.3
Reflection shellResolution: 1.68→1.73 Å / Rmerge(I) obs: 1.664 / Mean I/σ(I) obs: 2.3 / Num. unique obs: 2167 / CC1/2: 0.816 / Rpim(I) all: 0.645 / Rrim(I) all: 1.786 / % possible all: 100

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Processing

Software
NameVersionClassification
REFMAC5.8.0425refinement
pointlessdata scaling
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.68→45.78 Å / Cor.coef. Fo:Fc: 0.971 / Cor.coef. Fo:Fc free: 0.963 / SU B: 1.901 / SU ML: 0.062 / Cross valid method: THROUGHOUT / ESU R: 0.09 / ESU R Free: 0.09 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.1997 2147 4.9 %RANDOM
Rwork0.17019 ---
obs0.17169 41485 99.99 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 32.343 Å2
Baniso -1Baniso -2Baniso -3
1--0.23 Å20 Å2-0 Å2
2--1.58 Å2-0 Å2
3----1.35 Å2
Refinement stepCycle: 1 / Resolution: 1.68→45.78 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2505 0 77 211 2793
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0122741
X-RAY DIFFRACTIONr_bond_other_d0.0010.0162669
X-RAY DIFFRACTIONr_angle_refined_deg1.4291.8543706
X-RAY DIFFRACTIONr_angle_other_deg0.4961.7866174
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.9755331
X-RAY DIFFRACTIONr_dihedral_angle_2_deg5.342519
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.88410500
X-RAY DIFFRACTIONr_dihedral_angle_4_deg
X-RAY DIFFRACTIONr_chiral_restr0.070.2405
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.023151
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02604
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_it2.5343.1781286
X-RAY DIFFRACTIONr_mcbond_other2.5173.1741285
X-RAY DIFFRACTIONr_mcangle_it3.9075.6831611
X-RAY DIFFRACTIONr_mcangle_other3.9075.6851612
X-RAY DIFFRACTIONr_scbond_it3.2023.5971455
X-RAY DIFFRACTIONr_scbond_other3.2013.5981456
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other5.1776.3882089
X-RAY DIFFRACTIONr_long_range_B_refined7.27131.943064
X-RAY DIFFRACTIONr_long_range_B_other7.2431.863014
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.68→1.724 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.274 150 -
Rwork0.266 3013 -
obs--100 %

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