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- PDB-9p9u: EGFR-KDD with compound2 -

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Basic information

Entry
Database: PDB / ID: 9p9u
TitleEGFR-KDD with compound2
ComponentsEpidermal growth factor receptor
KeywordsONCOPROTEIN / Receptor tyrosine kinases / epidermal growth factor receptor / growth factor signaling / dimerization
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 / EGFR interacts with phospholipase C-gamma / epidermal growth factor receptor activity / epidermal growth factor binding / response to UV-A / regulation of peptidyl-tyrosine phosphorylation ...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 / EGFR interacts with phospholipase C-gamma / epidermal growth factor receptor activity / epidermal growth factor binding / response to UV-A / regulation of peptidyl-tyrosine phosphorylation / PLCG1 events in ERBB2 signaling / ERBB2-EGFR signaling pathway / PTK6 promotes HIF1A stabilization / ERBB2 Activates PTK6 Signaling / Signaling by EGFR / intracellular vesicle / negative regulation of epidermal growth factor receptor signaling pathway / ERBB2 Regulates Cell Motility / Developmental Lineage of Mammary Gland Myoepithelial Cells / protein insertion into membrane / Signaling by ERBB4 / Respiratory syncytial virus (RSV) attachment and entry / PI3K events in ERBB2 signaling / positive regulation of phosphorylation / positive regulation of peptidyl-serine phosphorylation / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / MAP kinase kinase kinase activity / GAB1 signalosome / protein tyrosine kinase activator activity / ossification / positive regulation of G1/S transition of mitotic cell cycle / Signaling by ERBB2 / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / transmembrane receptor protein tyrosine kinase activity / positive regulation of epithelial cell proliferation / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / GRB2 events in ERBB2 signaling / cellular response to amino acid stimulus / SHC1 events in ERBB2 signaling / positive regulation of fibroblast proliferation / cellular response to epidermal growth factor stimulus / basal plasma membrane / positive regulation of DNA replication / positive regulation of DNA repair / phosphatidylinositol 3-kinase/protein kinase B signal transduction / Signal transduction by L1 / cellular response to estradiol stimulus / positive regulation of protein localization to plasma membrane / negative regulation of protein catabolic process / clathrin-coated endocytic vesicle membrane / NOTCH3 Activation and Transmission of Signal to the Nucleus / cell-cell adhesion / Signaling by ERBB2 TMD/JMD mutants / EGFR downregulation / Constitutive Signaling by EGFRvIII / receptor protein-tyrosine kinase / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / positive regulation of miRNA transcription / positive regulation of protein phosphorylation / cell junction / epidermal growth factor receptor signaling pathway / kinase binding / ruffle membrane / Downregulation of ERBB2 signaling / Constitutive Signaling by Aberrant PI3K in Cancer / HCMV Early Events / positive regulation of canonical Wnt signaling pathway / actin filament binding / PIP3 activates AKT signaling / neuron differentiation / transmembrane signaling receptor activity / positive regulation of cell growth / Cargo recognition for clathrin-mediated endocytosis / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / Clathrin-mediated endocytosis / nuclear membrane / ATPase binding / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / virus receptor activity / RAF/MAP kinase cascade / protein tyrosine kinase activity / double-stranded DNA binding / early endosome membrane / protein phosphatase binding / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / basolateral plasma membrane / positive regulation of MAPK cascade / learning or memory / positive regulation of ERK1 and ERK2 cascade / signaling receptor complex / cell surface receptor signaling pathway / Extra-nuclear estrogen signaling / endosome / endosome membrane / positive regulation of cell migration / cadherin binding / membrane raft
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 / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / 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
Chem-6JS / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.27 Å
AuthorsHan, L. / Petrova, Z.O. / Lemmon, M.A.
Funding support United States, 3items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35-GM122485 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)R01-CA198164 United States
National Institutes of Health/National Institute of Dental and Craniofacial Research (NIH/NIDCR)P50-DE030707 United States
CitationJournal: Structure / Year: 2026
Title: The role of kinase domain dimerization in EGFR activation.
Authors: Zaritza O Petrova / Long Han / Yuko Tsutsui / Joshua B Sheetz / Kumar D Ashtekar / Mark A Lemmon /
Abstract: The epidermal growth factor receptor (EGFR) was among the first receptor tyrosine kinases (RTKs) shown to be activated by ligand-induced dimerization. Structural studies explain how ligand binding ...The epidermal growth factor receptor (EGFR) was among the first receptor tyrosine kinases (RTKs) shown to be activated by ligand-induced dimerization. Structural studies explain how ligand binding induces the dimerization of EGFR's extracellular region. Unlike other RTKs, EGFR's intracellular tyrosine kinase domain (TKD) is activated allosterically in an asymmetric dimer that is observed crystallographically, but not in cryo-EM studies of intact EGFR. Here, we show that this asymmetric TKD dimer forms only transiently - explaining its lack of definition by cryo-EM. By engineering an asymmetric TKD dimer and studying a TKD-duplicated lung cancer EGFR variant, we show that TKD dimerization increases kinase activity by several hundred-fold. We were also able to stabilize and visualize discrete asymmetric EGFR TKD dimers at high resolution using cryo-EM. Our findings argue that oncogenic mutations activate EGFR primarily by promoting TKD dimerization, and suggest that the transient nature of EGFR TKD dimers may allow biased EGFR signaling.
History
DepositionJun 24, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 19, 2025Provider: repository / Type: Initial release
Revision 1.0Nov 19, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Nov 19, 2025Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
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Revision 1.0Nov 19, 2025Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Nov 19, 2025Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Dec 17, 2025Group: Data collection / Database references / Structure summary
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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)77,8843
Polymers77,1371
Non-polymers7472
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

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


Mass: 77137.133 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: Insect BA phytoplasma (bacteria)
References: UniProt: P00533, receptor protein-tyrosine kinase
#2: Chemical ChemComp-6JS / 3-(furan-2-yl)-N-[5-(furan-2-yl)-2-methoxyphenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine


Mass: 373.365 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C20H15N5O3 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: EGFR-KDD and compound 2 / Type: COMPLEX
Details: epidermal growth factor receptor kinase domain duplicated and compound 2
Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Insect BA phytoplasma (bacteria)
Buffer solutionpH: 7.5
SpecimenConc.: 1.1 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R2/1
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2500 nm / Nominal defocus min: 1000 nm / Cs: 2.7 mm / C2 aperture diameter: 50 µm
Image recordingElectron dose: 45 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM software
IDNameVersionCategory
4cryoSPARC4.3CTF correction
13cryoSPARC4.33D reconstruction
CTF correctionType: NONE
Particle selectionNum. of particles selected: 16778798
3D reconstructionResolution: 3.27 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 337652 / Symmetry type: POINT
RefinementHighest resolution: 3.27 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0044509
ELECTRON MICROSCOPYf_angle_d0.696106
ELECTRON MICROSCOPYf_dihedral_angle_d5.111594
ELECTRON MICROSCOPYf_chiral_restr0.045685
ELECTRON MICROSCOPYf_plane_restr0.006755

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