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- EMDB-71423: EGFR-KDD with compound2 -

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Basic information

Entry
Database: EMDB / ID: EMD-71423
TitleEGFR-KDD with compound2
Map data
Sample
  • Complex: EGFR-KDD and compound 2
    • Protein or peptide: Epidermal growth factor receptor
  • Ligand: 3-(furan-2-yl)-N-[5-(furan-2-yl)-2-methoxyphenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine
KeywordsReceptor tyrosine kinases / epidermal growth factor receptor / growth factor signaling / dimerization / ONCOPROTEIN
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 / epidermal growth factor binding / regulation of peptidyl-tyrosine phosphorylation / 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 / epidermal growth factor binding / regulation of peptidyl-tyrosine phosphorylation / response to UV-A / ubiquitin-dependent endocytosis / PLCG1 events in ERBB2 signaling / morphogenesis of an epithelial fold / PTK6 promotes HIF1A stabilization / ERBB2 Activates PTK6 Signaling / digestive tract morphogenesis / ERBB2-EGFR signaling pathway / Signaling by EGFR / eyelid development in camera-type eye / intracellular vesicle / cerebral cortex cell migration / ERBB2 Regulates Cell Motility / Developmental Lineage of Mammary Gland Myoepithelial Cells / protein insertion into membrane / protein tyrosine kinase activator activity / Signaling by ERBB4 / Respiratory syncytial virus (RSV) attachment and entry / negative regulation of epidermal growth factor receptor signaling pathway / PI3K events in ERBB2 signaling / hair follicle development / positive regulation of phosphorylation / positive regulation of peptidyl-serine phosphorylation / MAP kinase kinase kinase activity / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / embryonic placenta development / GAB1 signalosome / salivary gland morphogenesis / xenobiotic transport / positive regulation of G1/S transition of mitotic cell cycle / positive regulation of epidermal growth factor receptor signaling pathway / Signaling by ERBB2 / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / transmembrane receptor protein tyrosine kinase activity / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / epithelial cell proliferation / GRB2 events in ERBB2 signaling / SHC1 events in ERBB2 signaling / basal plasma membrane / ossification / cellular response to epidermal growth factor stimulus / positive regulation of DNA replication / positive regulation of epithelial cell proliferation / positive regulation of DNA repair / Signal transduction by L1 / positive regulation of protein localization to plasma membrane / cellular response to estradiol stimulus / phosphatidylinositol 3-kinase/protein kinase B signal transduction / cellular response to amino acid stimulus / sperm end piece / NOTCH3 Activation and Transmission of Signal to the Nucleus / clathrin-coated endocytic vesicle membrane / Signaling by ERBB2 TMD/JMD mutants / EGFR downregulation / receptor protein-tyrosine kinase / Constitutive Signaling by EGFRvIII / negative regulation of protein catabolic process / cell-cell adhesion / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / positive regulation of protein phosphorylation / positive regulation of miRNA transcription / positive regulation of fibroblast proliferation / cell morphogenesis / epidermal growth factor receptor signaling pathway / ruffle membrane / kinase binding / Downregulation of ERBB2 signaling / Constitutive Signaling by Aberrant PI3K in Cancer / neuron differentiation / HCMV Early Events / actin filament binding / cell junction / transmembrane signaling receptor activity / PIP3 activates AKT signaling / positive regulation of canonical Wnt signaling pathway / Cargo recognition for clathrin-mediated endocytosis / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / Clathrin-mediated endocytosis / ATPase binding / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / sperm principal piece / virus receptor activity / RAF/MAP kinase cascade / positive regulation of cell growth / protein tyrosine kinase activity / double-stranded DNA binding / sperm midpiece / early 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 / 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
Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.27 Å
AuthorsHan L / Petrova ZO / Lemmon MA
Funding support United States, 3 items
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, 2025-
Header (metadata) releaseNov 19, 2025-
Map releaseNov 19, 2025-
UpdateJun 3, 2026-
Current statusJun 3, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_71423.png

Downloads & links

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Map

FileDownload / File: emd_71423.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 300 pix.
= 249.6 Å		0.83 Å/pix.
x 300 pix.
= 249.6 Å		0.83 Å/pix.
x 300 pix.
= 249.6 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.832 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.1
Minimum - Maximum-0.0016856851 - 2.7732763
Average (Standard dev.)0.00072786934 (±0.021356657)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 249.6 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_71423_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_71423_half_map_2.map
Projections & Slices
AxesZYX

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Histogram

Histogram (log scale)

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Sample components

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Entire : EGFR-KDD and compound 2

EntireName: EGFR-KDD and compound 2
Components
  • Complex: EGFR-KDD and compound 2
    • Protein or peptide: Epidermal growth factor receptor
  • Ligand: 3-(furan-2-yl)-N-[5-(furan-2-yl)-2-methoxyphenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine

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Supramolecule #1: EGFR-KDD and compound 2

SupramoleculeName: EGFR-KDD and compound 2 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Details: epidermal growth factor receptor kinase domain duplicated and compound 2
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Epidermal growth factor receptor

MacromoleculeName: Epidermal growth factor receptor / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO / EC number: receptor protein-tyrosine kinase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 77.137133 KDa
Recombinant expressionOrganism: Insect BA phytoplasma (bacteria)
SequenceString: GEAPNQALLR ILKETEFKKI KVLGSGAFGT VYKGLWIPEG EKVKIPVAIK ELREATSPKA NKEILDEAYV MASVDNPHVC RLLGICLTS TVQLITQLMP FGCLLDYVRE HKDNIGSQYL LNWCVQIAKG MNYLEDRRLV HRDLAARNVL VKTPQHVKIT D FGLAKLLG ...String:
GEAPNQALLR ILKETEFKKI KVLGSGAFGT VYKGLWIPEG EKVKIPVAIK ELREATSPKA NKEILDEAYV MASVDNPHVC RLLGICLTS TVQLITQLMP FGCLLDYVRE HKDNIGSQYL LNWCVQIAKG MNYLEDRRLV HRDLAARNVL VKTPQHVKIT D FGLAKLLG AEEKEYHAEG GKVPIKWMAL ESILHRIYTH QSDVWSYGVT VWELMTFGSK PYDGIPASEI SSILEKGERL PQ PPICTID VYMIMVKCWM IDADSRPKFR ELIIEFSKMA RDPQRYLVIQ GDERMHLPSP TDSNFYRALM DEEDMDDVVD ADE YLIPQQ GFFSSPSTSR TPLLSSLLVE PLTPSGEAPN QALLRILKET EFKKIKVLGS GAFGTVYKGL WIPEGEKVKI PVAI KELRE ATSPKANKEI LDEAYVMASV DNPHVCRLLG ICLTSTVQLI TQLMPFGCLL DYVREHKDNI GSQYLLNWCV QIAKG MNYL EDRRLVHRDL AARNVLVKTP QHVKITDFGL AKLLGAEEKE YHAEGGKVPI KWMALESILH RIYTHQSDVW SYGVTV WEL MTFGSKPYDG IPASEISSIL EKGERLPQPP ICTIDVYMIM VKCWMIDADS RPKFRELIIE FSKMARDPQR YLVIQGD ER MHLPSPTDSN FYRALMDEED MDDVVDADEY LIPQQG

UniProtKB: Epidermal growth factor receptor, Epidermal growth factor receptor

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Macromolecule #2: 3-(furan-2-yl)-N-[5-(furan-2-yl)-2-methoxyphenyl]-1H-pyrazolo[3,4...

MacromoleculeName: 3-(furan-2-yl)-N-[5-(furan-2-yl)-2-methoxyphenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine
type: ligand / ID: 2 / Number of copies: 2 / Formula: 6JS
Molecular weightTheoretical: 373.365 Da
Chemical component information

ChemComp-6JS:
3-(furan-2-yl)-N-[5-(furan-2-yl)-2-methoxyphenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration1.1 mg/mL
BufferpH: 7.5
GridModel: Quantifoil R2/1 / Material: GOLD / Mesh: 300
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 45.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 50.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 16778798
CTF correctionSoftware - Name: cryoSPARC (ver. 4.3) / Type: NONE
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.27 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4.3) / Number images used: 337652
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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