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- PDB-9frd: Wildtype EGFR bound with Compound 23 -

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Basic information

Entry
Database: PDB / ID: 9frd
TitleWildtype EGFR bound with Compound 23
ComponentsEpidermal growth factor receptor
KeywordsONCOPROTEIN / Kinase / EGFR wildtype
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 / response to UV-A / tongue development / PLCG1 events in ERBB2 signaling / midgut development / ERBB2-EGFR signaling pathway / digestive tract morphogenesis / hydrogen peroxide metabolic process / PTK6 promotes HIF1A stabilization / morphogenesis of an epithelial fold / 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 / positive regulation of cyclin-dependent protein serine/threonine kinase activity / Signaling by ERBB4 / protein tyrosine kinase activator activity / Respiratory syncytial virus (RSV) attachment and entry / regulation of peptidyl-tyrosine phosphorylation / 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 / embryonic placenta development / positive regulation of bone resorption / positive regulation of phosphorylation / salivary gland morphogenesis / peptidyl-tyrosine autophosphorylation / 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 / histone H3Y41 kinase activity / histone H2AXY142 kinase activity / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / GRB2 events in ERBB2 signaling / cellular response to epidermal growth factor stimulus / SHC1 events in ERBB2 signaling / cellular response to dexamethasone stimulus / positive regulation of synaptic transmission, glutamatergic / ossification / positive regulation of DNA repair / positive regulation of peptidyl-serine phosphorylation / neuron projection morphogenesis / positive regulation of superoxide anion generation / positive regulation of epithelial cell proliferation / basal plasma membrane / liver regeneration / epithelial cell proliferation / Signal transduction by L1 / neurogenesis / positive regulation of DNA replication / positive regulation of protein localization to plasma membrane / astrocyte activation / 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 / cell surface receptor protein tyrosine kinase signaling pathway / 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
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
: / 2,3-DIHYDROXY-1,4-DITHIOBUTANE / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.06 Å
AuthorsPagliarini, A.R. / Milgram, B.C. / Borrelli, D.R. / OHearn, E. / Huff, M.R. / Ladd, B. / Brooijmans, N. / Henderson, J.A. / Hilbert, B.J. / Wang, W. / Ito, T.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2025
Title: Discovery of STX-721, a Covalent, Potent, and Highly Mutant-Selective EGFR/HER2 Exon20 Insertion Inhibitor for the Treatment of Non-Small Cell Lung Cancer.
Authors: Milgram, B.C. / Borrelli, D.R. / Brooijmans, N. / Henderson, J.A. / Hilbert, B.J. / Huff, M.R. / Ito, T. / Jackson, E.L. / Jonsson, P. / Ladd, B. / O'Hearn, E.L. / Pagliarini, R.A. / ...Authors: Milgram, B.C. / Borrelli, D.R. / Brooijmans, N. / Henderson, J.A. / Hilbert, B.J. / Huff, M.R. / Ito, T. / Jackson, E.L. / Jonsson, P. / Ladd, B. / O'Hearn, E.L. / Pagliarini, R.A. / Roberts, S.A. / Ronseaux, S. / Stuart, D.D. / Wang, W. / Guzman-Perez, A.
History
DepositionJun 18, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 29, 2025Provider: repository / Type: Initial release
Revision 1.1Feb 26, 2025Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,2144
Polymers37,5791
Non-polymers6353
Water2,306128
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area400 Å2
ΔGint-9 kcal/mol
Surface area15550 Å2
Unit cell
Length a, b, c (Å)145.160, 145.160, 145.160
Angle α, β, γ (deg.)90.000, 90.000, 90.000
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-DTT / 2,3-DIHYDROXY-1,4-DITHIOBUTANE / 1,4-DITHIOTHREITOL


Mass: 154.251 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H10O2S2
#3: Chemical ChemComp-A1IEZ / (7~{S})-3-[(3-chloranyl-2-methoxy-phenyl)amino]-2-(3-fluoranylpyridin-4-yl)-7-(2-methoxyethyl)-1,5,6,7-tetrahydropyrrolo[3,2-c]pyridin-4-one


Mass: 444.886 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H22ClFN4O3 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-CL / CHLORIDE ION


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


Mass: 18.015 Da / Num. of mol.: 128 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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: 3.39 Å3/Da / Density % sol: 63.73 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: sodium tartrate, sodium acetate, ammonium chloride

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1.00003231311 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Feb 10, 2021
RadiationMonochromator: M / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.00003231311 Å / Relative weight: 1
ReflectionResolution: 2.057→72.69 Å / Num. obs: 802325 / % possible obs: 100 % / Redundancy: 25.3 % / CC1/2: 1 / Net I/σ(I): 22.3
Reflection shellResolution: 2.057→2.092 Å / Num. unique obs: 1561 / CC1/2: 0.559

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Processing

Software
NameVersionClassification
REFMAC5.8.0267refinement
PDB_EXTRACT3.28data extraction
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.06→72.69 Å / Cor.coef. Fo:Fc: 0.973 / Cor.coef. Fo:Fc free: 0.963 / SU B: 6.657 / SU ML: 0.089 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.13 / ESU R Free: 0.123 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: U VALUES : WITH TLS ADDED HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.1965 1797 5.7 %RANDOM
Rwork0.1676 ---
obs0.1692 29892 100 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 158.74 Å2 / Biso mean: 62.327 Å2 / Biso min: 36.88 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å20 Å20 Å2
2--0 Å20 Å2
3---0 Å2
Refinement stepCycle: final / Resolution: 2.06→72.69 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2465 0 40 131 2636
Biso mean--65.94 61.39 -
Num. residues----309
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0132582
X-RAY DIFFRACTIONr_bond_other_d0.0020.0172506
X-RAY DIFFRACTIONr_angle_refined_deg1.5711.6583499
X-RAY DIFFRACTIONr_angle_other_deg1.2561.5925794
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.0755315
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.94322.283127
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.0915.032473
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.7561515
X-RAY DIFFRACTIONr_chiral_restr0.0790.2334
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.022831
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02550
X-RAY DIFFRACTIONr_mcbond_it2.6954.041242
X-RAY DIFFRACTIONr_mcbond_other2.6934.0381241
X-RAY DIFFRACTIONr_mcangle_it3.8316.0371551
LS refinement shellResolution: 2.06→2.11 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.271 144 -
Rwork0.267 2179 -
obs--100 %
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)
17.8121-5.34326.50467.1326-5.26258.22110.38520.3008-0.1868-0.3145-0.04360.17310.5033-0.1113-0.34150.0588-0.0346-0.00760.0998-0.04830.1886-66.92743.54-0.638
22.86191.15522.1374.98051.24124.00740.1051-0.1744-0.25120.3799-0.0158-0.61670.31190.2469-0.08920.20460.0141-0.06920.1356-0.03290.1924-51.96428.2965.015
32.13860.27850.27252.91490.87563.1878-0.03390.0782-0.16840.02270.1097-0.19390.10.0582-0.07580.0355-0.0186-0.00680.0272-0.02490.0577-61.14721.203-17.726
412.1184-6.45055.559915.7813-4.33777.37580.3534-0.02740.1030.4943-0.3544-0.06840.1215-0.02620.0010.3377-0.02150.03850.30160.00240.3638-63.86921.29412.29
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A1 - 705
2X-RAY DIFFRACTION2A706 - 794
3X-RAY DIFFRACTION3A795 - 1000
4X-RAY DIFFRACTION4A1001 - 1030

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