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- PDB-2m20: EGFR transmembrane - juxtamembrane (TM-JM) segment in bicelles: M... -

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Basic information

Entry
Database: PDB / ID: 2m20
TitleEGFR transmembrane - juxtamembrane (TM-JM) segment in bicelles: MD guided NMR refined structure.
ComponentsEpidermal growth factor receptor
KeywordsSIGNALING PROTEIN / Transmembrane / Cell Signaling / Juxtamembrane
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
Single alpha-helices involved in coiled-coils or other helix-helix interfaces - #2930 / : / Epidermal growth factor receptor transmembrane-juxtamembrane segment / Tyrosine protein kinase, EGF/ERB/XmrK receptor / Growth factor receptor domain 4 / Growth factor receptor domain IV / Single alpha-helices involved in coiled-coils or other helix-helix interfaces / Receptor L-domain / Furin-like cysteine-rich domain / Receptor L-domain superfamily ...Single alpha-helices involved in coiled-coils or other helix-helix interfaces - #2930 / : / Epidermal growth factor receptor transmembrane-juxtamembrane segment / Tyrosine protein kinase, EGF/ERB/XmrK receptor / Growth factor receptor domain 4 / Growth factor receptor domain IV / Single alpha-helices involved in coiled-coils or other helix-helix interfaces / 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 / : / Helix non-globular / Special / 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)
MethodSOLUTION NMR / simulated annealing
Model detailslowest energy, model 1
AuthorsEndres, N.F. / Das, R. / Smith, A. / Arkhipov, A. / Kovacs, E. / Huang, Y. / Pelton, J.G. / Shan, Y. / Shaw, D.E. / Wemmer, D.E. ...Endres, N.F. / Das, R. / Smith, A. / Arkhipov, A. / Kovacs, E. / Huang, Y. / Pelton, J.G. / Shan, Y. / Shaw, D.E. / Wemmer, D.E. / Groves, J.T. / Kuriyan, J.
Citation
Journal: Cell(Cambridge,Mass.) / Year: 2013
Title: Conformational Coupling across the Plasma Membrane in Activation of the EGF Receptor.
Authors: Endres, N.F. / Das, R. / Smith, A.W. / Arkhipov, A. / Kovacs, E. / Huang, Y. / Pelton, J.G. / Shan, Y. / Shaw, D.E. / Wemmer, D.E. / Groves, J.T. / Kuriyan, J.
#1: Journal: To be Published
Title: Architecture and Membrane Interactions of the EGF Receptor.
Authors: Endres, N.F. / Das, R. / Smith, A. / Arkhipov, A. / Kovacs, E. / Huang, Y. / Pelton, J.G. / Shan, Y. / Shaw, D.E. / Wemmer, D.E. / Groves, J.T. / Kuriyan, J.
History
DepositionDec 11, 2012Deposition site: BMRB / Processing site: RCSB
Revision 1.0Feb 20, 2013Provider: repository / Type: Initial release
Revision 1.1May 1, 2024Group: Data collection / Database references
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_nmr_software / pdbx_nmr_spectrometer / struct_ref_seq_dif
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_nmr_software.name / _pdbx_nmr_spectrometer.model / _struct_ref_seq_dif.details

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Epidermal growth factor receptor
B: Epidermal growth factor receptor


Theoretical massNumber of molelcules
Total (without water)13,5592
Polymers13,5592
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1476.1 Å2
ΔGint-10.6 kcal/mol
Surface area12144.7 Å2
MethodPISA
NMR ensembles
DataCriteria
Number of conformers (submitted / calculated)10 / 50structures with the lowest energy
RepresentativeModel #1lowest energy

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Components

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


Mass: 6779.251 Da / Num. of mol.: 2
Fragment: EGFR Transmembrane-Juxtamembrane segment, UNP residues 642-697
Mutation: M9L (M650 in UNP P00533), M27I (M668 in UNP P00533)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EGFR, ERBB, ERBB1, HER1 / Plasmid: pMMHb / Production host: Escherichia coli (E. coli) / References: UniProt: P00533

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Experimental details

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Experiment

ExperimentMethod: SOLUTION NMR
NMR experiment
Conditions-IDExperiment-IDSolution-IDType
1122D 1H-15N HSQC
1222D 1H-13C HSQC
1313D HNCO
1413D HNCA
1513D HN(CA)CB
1613D HN(CO)CA
1723D 1H-15N NOESY
1823D 1H-13C NOESY
1923D (H)CCH-COSY
11023D (H)CCH-TOCSY
11133D 15N-13C F1 filtered/F3 edited NOESY-HSQC
11212D 1H-15N TROSY

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Sample preparation

Details
Solution-IDContentsSolvent system
10.300 mM [U-100% 13C; U-100% 15N; U-80% 2H] EGFR TM-JM, 50 mM MES, 5 mM TCEP, 1 mM EDTA, 0.05 mM AMESF, 10 % [U-2H] D2O, 0.02 % sodium azide, 9.4 mM [U-99% 2H] DMPC (D54), 37.98 mM [U-99% 2H] DHPC (D22), 90% H2O/10% D2O90% H2O/10% D2O
20.300 mM [U-100% 13C; U-100% 15N] EGFR TM-JM, 50 mM MES, 5 mM TCEP, 1 mM EDTA, 0.05 mM AMESF, 10 % [U-2H] D2O, 0.02 % sodium azide, 9.4 mM [U-99% 2H] DMPC (D54), 37.98 mM [U-99% 2H] DHPC (D22), 90% H2O/10% D2O90% H2O/10% D2O
30.300 mM EGFR TM-JM, 50 mM MES, 5 mM TCEP, 1 mM EDTA, 0.05 mM AMESF, 10 % [U-2H] D2O, 0.02 % sodium azide, 18.8 mM [U-99% 2H] DMPC (D54), 77.86 mM [U-99% 2H] DHPC (D22), 0.300 mM EGFR TM-JM, 90% H2O/10% D2O90% H2O/10% D2O
Sample
Conc. (mg/ml)ComponentIsotopic labelingSolution-ID
0.300 mMEGFR TM-JM-1[U-100% 13C; U-100% 15N; U-80% 2H]1
50 mMMES-21
5 mMTCEP-31
1 mMEDTA-41
0.05 mMAMESF-51
10 %D2O-6[U-2H]1
0.02 %sodium azide-71
9.4 mMDMPC (D54)-8[U-99% 2H]1
37.98 mMDHPC (D22)-9[U-99% 2H]1
0.300 mMEGFR TM-JM-10[U-100% 13C; U-100% 15N]2
50 mMMES-112
5 mMTCEP-122
1 mMEDTA-132
0.05 mMAMESF-142
10 %D2O-15[U-2H]2
0.02 %sodium azide-162
9.4 mMDMPC (D54)-17[U-99% 2H]2
37.98 mMDHPC (D22)-18[U-99% 2H]2
0.300 mMEGFR TM-JM-193
50 mMMES-203
5 mMTCEP-213
1 mMEDTA-223
0.05 mMAMESF-233
10 %D2O-24[U-2H]3
0.02 %sodium azide-253
18.8 mMDMPC (D54)-26[U-99% 2H]3
77.86 mMDHPC (D22)-27[U-99% 2H]3
0.300 mMEGFR TM-JM-283
Sample conditionsIonic strength: 0.05 / pH: 6.2 / Pressure: ambient / Temperature: 312 K

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NMR measurement

NMR spectrometer
TypeManufacturerModelField strength (MHz)Spectrometer-ID
Bruker Avance IIBrukerAVANCE II9001
Bruker AvanceBrukerAVANCE8002
Bruker AvanceBrukerAVANCE6003

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Processing

NMR software
NameVersionDeveloperClassification
TopSpinv1.3Bruker Biospincollection
NMRDrawv3.0Delaglio, Grzesiek, Vuister, Zhu, Pfeifer and Baxprocessing
NMRPipev3.0Delaglio, Grzesiek, Vuister, Zhu, Pfeifer and Baxprocessing
Sparkyv3.114Goddardchemical shift assignment
Sparkyv3.114Goddardpeak picking
TALOS+Yang Shen, Frank Delaglio, Gabriel Cornilescu, and Ad Bax,data analysis
CNSv1.3Brunger, Adams, Clore, Gros, Nilges and Readstructure solution
CNSv1.3Brunger, Adams, Clore, Gros, Nilges and Readrefinement
ProcheckNMRLaskowski and MacArthurdata analysis
PSVSBhattacharya and Montelionedata analysis
MOLMOLKoradi, Billeter and Wuthrichdata analysis
RefinementMethod: simulated annealing / Software ordinal: 1
Details: 1. The TM-JM dimer structure was calculated with 38 interchain NOEs (19 interchain NOE restraint per monomer). There are too few interchain NOEs to determine the configuration of the TM-JM ...Details: 1. The TM-JM dimer structure was calculated with 38 interchain NOEs (19 interchain NOE restraint per monomer). There are too few interchain NOEs to determine the configuration of the TM-JM dimer unambiguously. Therefore, we used observations from molecular dynamics simulations of the TM-JM segment in DMPC lipid bilayers (see Arkhipov et al. 2013, Cell in press; companion paper to the paper describing the analysis of the TM-JM structure in an experimental context), and selected a initial structure of the TM-JM dimer with a dimeric conformation of right handed crossing angles that was stable during the MD simulations. It was then refined using NMR restraints. 2. The secondary structure analysis suggested that the juxtamembrane -A segment has a 30% probability of helix formation. In order to model the juxtamembrane dimer we assumed that the juxtamembrane-A segment only forms a dimer when both juxtamembrane segments are helical.
NMR constraintsNOE constraints total: 580 / NOE long range total count: 38 / Hydrogen bond constraints total count: 36 / Protein chi angle constraints total count: 22 / Protein phi angle constraints total count: 92 / Protein psi angle constraints total count: 92
NMR representativeSelection criteria: lowest energy
NMR ensembleConformer selection criteria: structures with the lowest energy
Conformers calculated total number: 50 / Conformers submitted total number: 10

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