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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


response to hydroxyisoflavone / multivesicular body, internal vesicle lumen / positive regulation of prolactin secretion / negative regulation of cardiocyte differentiation / positive regulation of protein kinase C activity / diterpenoid metabolic process / Shc-EGFR complex / ovulation cycle / Inhibition of Signaling by Overexpressed EGFR / epidermal growth factor receptor activity ...response to hydroxyisoflavone / multivesicular body, internal vesicle lumen / positive regulation of prolactin secretion / negative regulation of cardiocyte differentiation / positive regulation of protein kinase C activity / diterpenoid metabolic process / Shc-EGFR complex / ovulation cycle / Inhibition of Signaling by Overexpressed EGFR / epidermal growth factor receptor activity / EGFR interacts with phospholipase C-gamma / positive regulation of mucus secretion / response to UV-A / epidermal growth factor binding / PLCG1 events in ERBB2 signaling / tongue development / midgut development / ERBB2-EGFR signaling pathway / hydrogen peroxide metabolic process / PTK6 promotes HIF1A stabilization / digestive tract morphogenesis / morphogenesis of an epithelial fold / ERBB2 Activates PTK6 Signaling / intracellular vesicle / Signaling by EGFR / response to cobalamin / transmembrane receptor protein tyrosine kinase activator activity / protein tyrosine kinase activator activity / negative regulation of epidermal growth factor receptor signaling pathway / Signaling by ERBB4 / eyelid development in camera-type eye / regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / protein insertion into membrane / cerebral cortex cell migration / ERBB2 Regulates Cell Motility / Respiratory syncytial virus (RSV) attachment and entry / regulation of JNK cascade / : / PI3K events in ERBB2 signaling / positive regulation of cyclin-dependent protein serine/threonine kinase activity / negative regulation of mitotic cell cycle / hair follicle development / MAP kinase kinase kinase activity / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / embryonic placenta development / positive regulation of bone resorption / positive regulation of G1/S transition of mitotic cell cycle / GAB1 signalosome / salivary gland morphogenesis / peptidyl-tyrosine autophosphorylation / regulation of peptidyl-tyrosine phosphorylation / positive regulation of phosphorylation / positive regulation of glial cell proliferation / positive regulation of vasoconstriction / Signaling by ERBB2 / cellular response to epidermal growth factor stimulus / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / cellular response to cadmium ion / positive regulation of DNA repair / GRB2 events in ERBB2 signaling / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / transmembrane receptor protein tyrosine kinase activity / SHC1 events in ERBB2 signaling / positive regulation of synaptic transmission, glutamatergic / cellular response to dexamethasone stimulus / ossification / neurogenesis / regulation of ERK1 and ERK2 cascade / basal plasma membrane / neuron projection morphogenesis / positive regulation of superoxide anion generation / positive regulation of DNA replication / epithelial cell proliferation / Signal transduction by L1 / cellular response to estradiol stimulus / positive regulation of epithelial cell proliferation / NOTCH3 Activation and Transmission of Signal to the Nucleus / astrocyte activation / liver regeneration / positive regulation of protein localization to plasma membrane / EGFR downregulation / cellular response to amino acid stimulus / positive regulation of smooth muscle cell proliferation / Signaling by ERBB2 TMD/JMD mutants / positive regulation of MAP kinase activity / lung development / clathrin-coated endocytic vesicle membrane / Constitutive Signaling by EGFRvIII / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / epidermal growth factor receptor signaling pathway / negative regulation of protein catabolic process / receptor protein-tyrosine kinase / Downregulation of ERBB2 signaling / kinase binding / ruffle membrane / positive regulation of miRNA transcription / cell-cell adhesion
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 / Receptor L-domain / Furin-like cysteine-rich domain / Receptor L-domain superfamily / Furin-like cysteine rich region ...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 / Receptor L-domain / Furin-like cysteine-rich domain / Receptor L-domain superfamily / Furin-like cysteine rich region / Receptor L domain / Single alpha-helices involved in coiled-coils or other helix-helix interfaces / 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 / 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)
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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