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Yorodumi- EMDB-25563: Cryo-EM structure of the extracellular module of the full-length ... -
+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-25563 | |||||||||
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Title | Cryo-EM structure of the extracellular module of the full-length EGFR bound to TGF-alpha. "tips-juxtaposed" conformation | |||||||||
Map data | WT:TGFa_jux | |||||||||
Sample |
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Function / homology | Function and homology information Inhibition of Signaling by Overexpressed EGFR / EGFR interacts with phospholipase C-gamma / hepatocyte proliferation / ERBB2-EGFR signaling pathway / Signaling by EGFR / transmembrane receptor protein tyrosine kinase activator activity / Cargo concentration in the ER / COPII-mediated vesicle transport / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / epidermal growth factor receptor binding ...Inhibition of Signaling by Overexpressed EGFR / EGFR interacts with phospholipase C-gamma / hepatocyte proliferation / ERBB2-EGFR signaling pathway / Signaling by EGFR / transmembrane receptor protein tyrosine kinase activator activity / Cargo concentration in the ER / COPII-mediated vesicle transport / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / epidermal growth factor receptor binding / GAB1 signalosome / positive regulation of cell division / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / Complex I biogenesis / mammary gland alveolus development / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / Respiratory electron transport / positive regulation of epithelial cell proliferation / endoplasmic reticulum-Golgi intermediate compartment membrane / positive regulation of mitotic nuclear division / EGFR downregulation / : / clathrin-coated endocytic vesicle membrane / mitochondrial electron transport, NADH to ubiquinone / proton motive force-driven mitochondrial ATP synthesis / epidermal growth factor receptor signaling pathway / NADH dehydrogenase (ubiquinone) activity / growth factor activity / ER to Golgi transport vesicle membrane / aerobic respiration / Constitutive Signaling by Aberrant PI3K in Cancer / Cargo recognition for clathrin-mediated endocytosis / positive regulation of peptidyl-tyrosine phosphorylation / PIP3 activates AKT signaling / Clathrin-mediated endocytosis / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / RAF/MAP kinase cascade / basolateral plasma membrane / cytoplasmic vesicle / angiogenesis / Estrogen-dependent gene expression / Extra-nuclear estrogen signaling / positive regulation of MAPK cascade / cell surface receptor signaling pathway / receptor ligand activity / electron transfer activity / mitochondrial inner membrane / intracellular signal transduction / positive regulation of cell population proliferation / endoplasmic reticulum membrane / perinuclear region of cytoplasm / cell surface / extracellular space / extracellular region / plasma membrane Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.4 Å | |||||||||
Authors | Huang Y / Ognjenovic J / Karandur D / Miller K / Merk A / Subramaniam S / Kuriyan J | |||||||||
Funding support | Canada, United States, 2 items
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Citation | Journal: Elife / Year: 2021 Title: A molecular mechanism for the generation of ligand-dependent differential outputs by the epidermal growth factor receptor. Authors: Yongjian Huang / Jana Ognjenovic / Deepti Karandur / Kate Miller / Alan Merk / Sriram Subramaniam / John Kuriyan / Abstract: The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that couples the binding of extracellular ligands, such as EGF and transforming growth factor-α (TGF-α), to the initiation ...The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that couples the binding of extracellular ligands, such as EGF and transforming growth factor-α (TGF-α), to the initiation of intracellular signaling pathways. EGFR binds to EGF and TGF-α with similar affinity, but generates different signals from these ligands. To address the mechanistic basis of this phenomenon, we have carried out cryo-EM analyses of human EGFR bound to EGF and TGF-α. We show that the extracellular module adopts an ensemble of dimeric conformations when bound to either EGF or TGF-α. The two extreme states of this ensemble represent distinct ligand-bound quaternary structures in which the membrane-proximal tips of the extracellular module are either juxtaposed or separated. EGF and TGF-α differ in their ability to maintain the conformation with the membrane-proximal tips of the extracellular module separated, and this conformation is stabilized preferentially by an oncogenic EGFR mutation. Close proximity of the transmembrane helices at the junction with the extracellular module has been associated previously with increased EGFR activity. Our results show how EGFR can couple the binding of different ligands to differential modulation of this proximity, thereby suggesting a molecular mechanism for the generation of ligand-sensitive differential outputs in this receptor family. | |||||||||
History |
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-Structure visualization
Movie |
Movie viewer |
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Structure viewer | EM map: SurfViewMolmilJmol/JSmol |
Supplemental images |
-Downloads & links
-EMDB archive
Map data | emd_25563.map.gz | 122.7 MB | EMDB map data format | |
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Header (meta data) | emd-25563-v30.xml emd-25563.xml | 13.7 KB 13.7 KB | Display Display | EMDB header |
Images | emd_25563.png | 175.9 KB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-25563 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-25563 | HTTPS FTP |
-Validation report
Summary document | emd_25563_validation.pdf.gz | 418 KB | Display | EMDB validaton report |
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Full document | emd_25563_full_validation.pdf.gz | 417.5 KB | Display | |
Data in XML | emd_25563_validation.xml.gz | 7.3 KB | Display | |
Data in CIF | emd_25563_validation.cif.gz | 8.4 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-25563 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-25563 | HTTPS FTP |
-Related structure data
Related structure data | 7sz7MC 7sydC 7syeC 7sz0C 7sz1C 7sz5C C: citing same article (ref.) M: atomic model generated by this map |
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Similar structure data |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_25563.map.gz / Format: CCP4 / Size: 244.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Annotation | WT:TGFa_jux | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 1.0794 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
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-Supplemental data
-Sample components
-Entire : full-length human EGFR:TGF-alpha complex
Entire | Name: full-length human EGFR:TGF-alpha complex |
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Components |
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-Supramolecule #1: full-length human EGFR:TGF-alpha complex
Supramolecule | Name: full-length human EGFR:TGF-alpha complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all |
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Source (natural) | Organism: Homo sapiens (human) |
Recombinant expression | Organism: Homo sapiens (human) |
-Macromolecule #1: Epidermal growth factor receptor
Macromolecule | Name: Epidermal growth factor receptor / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO / EC number: receptor protein-tyrosine kinase |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 134.433328 KDa |
Recombinant expression | Organism: Homo sapiens (human) |
Sequence | String: MRPSGTAGAA LLALLAALCP ASRALEEKKV CQGTSNKLTQ LGTFEDHFLS LQRMFNNCEV VLGNLEITYV QRNYDLSFLK TIQEVAGYV LIALNTVERI PLENLQIIRG NMYYENSYAL AVLSNYDANK TGLKELPMRN LQEILHGAVR FSNNPALCNV E SIQWRDIV ...String: MRPSGTAGAA LLALLAALCP ASRALEEKKV CQGTSNKLTQ LGTFEDHFLS LQRMFNNCEV VLGNLEITYV QRNYDLSFLK TIQEVAGYV LIALNTVERI PLENLQIIRG NMYYENSYAL AVLSNYDANK TGLKELPMRN LQEILHGAVR FSNNPALCNV E SIQWRDIV SSDFLSNMSM DFQNHLGSCQ KCDPSCPNGS CWGAGEENCQ KLTKIICAQQ CSGRCRGKSP SDCCHNQCAA GC TGPRESD CLVCRKFRNE ATCKDTCPPL MLYNPTTYQM DVNPEGKYSF GATCVKKCPR NYVVTDHGSC VRACGADSYE MEE DGVRKC KKCEGPCRKV CNGIGIGEFK DSLSINATNI KHFKNCTSIS GDLHILPVAF RGDSFTHTPP LDPQELDILK TVKE ITGFL LIQAWPENRT DLHAFENLEI IRGRTKQHGQ FSLAVVSLNI TSLGLRSLKE ISDGDVIISG NKNLCYANTI NWKKL FGTS GQKTKIISNR GENSCKATGQ VCHALCSPEG CWGPEPRDCV SCRNVSRGRE CVDKCNLLEG EPREFVENSE CIQCHP ECL PQAMNITCTG RGPDNCIQCA HYIDGPHCVK TCPAGVMGEN NTLVWKYADA GHVCHLCHPN CTYGCTGPGL EGCPTNG PK IPSIATGMVG ALLLLLVVAL GIGLFMRRRH IVRKRTLRRL LQERELVEPL TPSGEAPNQA LLRILKETEF KKIKVLGS G AFGTVYKGLW IPEGEKVKIP VAIKELREAT SPKANKEILD EAYVMASVDN PHVCRLLGIC LTSTVQLITQ LMPFGCLLD YVREHKDNIG SQYLLNWCVQ IAKGMNYLED RRLVHRDLAA RNVLVKTPQH VKITDFGLAK LLGAEEKEYH AEGGKVPIKW MALESILHR IYTHQSDVWS YGVTVWELMT FGSKPYDGIP ASEISSILEK GERLPQPPIC TIDVYMIMVK CWMIDADSRP K FRELIIEF SKMARDPQRY LVIQGDERMH LPSPTDSNFY RALMDEEDMD DVVDADEYLI PQQGFFSSPS TSRTPLLSSL SA TSNNSTV ACIDRNGLQS CPIKEDSFLQ RYSSDPTGAL TEDSIDDTFL PVPEYINQSV PKRPAGSVQN PVYHNQPLNP APS RDPHYQ DPHSTAVGNP EYLNTVQPTC VNSTFDSPAH WAQKGSHQIS LDNPDYQQDF FPKEAKPNGI FKGSTAENAE YLRV APQSS EFIGA |
-Macromolecule #2: Transforming growth factor alpha
Macromolecule | Name: Transforming growth factor alpha / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 5.560246 KDa |
Recombinant expression | Organism: Escherichia coli (E. coli) |
Sequence | String: VVSHFNDCPD SHTQFCFHGT CRFLVQEDKP ACVCHSGYVG ARCEHADLLA |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Concentration | 0.5 mg/mL |
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Buffer | pH: 8 |
Grid | Model: UltrAuFoil R1.2/1.3 / Pretreatment - Type: PLASMA CLEANING |
Vitrification | Cryogen name: ETHANE |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K3 (6k x 4k) / Average electron dose: 50.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |