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- PDB-8hv5: Crystal structure of EGFR_DMX in complex with compound 7 -

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Basic information

Entry
Database: PDB / ID: 8hv5
TitleCrystal structure of EGFR_DMX in complex with compound 7
ComponentsEpidermal growth factor receptor
KeywordsTRANSFERASE / Epidermal growth factor receptor kinase / covalent fragments / mutant EGFR / anti-cancer
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 / regulation of peptidyl-tyrosine phosphorylation / epidermal growth factor binding / 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 / regulation of peptidyl-tyrosine phosphorylation / epidermal growth factor binding / response to UV-A / PLCG1 events in ERBB2 signaling / ERBB2-EGFR signaling pathway / morphogenesis of an epithelial fold / PTK6 promotes HIF1A stabilization / ERBB2 Activates PTK6 Signaling / digestive tract morphogenesis / Signaling by EGFR / intracellular vesicle / 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 / Respiratory syncytial virus (RSV) attachment and entry / Signaling by ERBB4 / PI3K events in ERBB2 signaling / positive regulation of phosphorylation / positive regulation of peptidyl-serine phosphorylation / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / hair follicle development / MAP kinase kinase kinase activity / GAB1 signalosome / positive regulation of G1/S transition of mitotic cell cycle / embryonic placenta development / salivary gland morphogenesis / Signaling by ERBB2 / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / EGFR Transactivation by Gastrin / transmembrane receptor protein tyrosine kinase activity / GRB2 events in ERBB2 signaling / SHC1 events in ERBB2 signaling / ossification / NOTCH3 Activation and Transmission of Signal to the Nucleus / positive regulation of DNA repair / basal plasma membrane / cellular response to epidermal growth factor stimulus / EGFR downregulation / positive regulation of DNA replication / epithelial cell proliferation / positive regulation of epithelial cell proliferation / Signal transduction by L1 / positive regulation of protein localization to plasma membrane / cellular response to amino acid stimulus / phosphatidylinositol 3-kinase/protein kinase B signal transduction / cellular response to estradiol stimulus / clathrin-coated endocytic vesicle membrane / Signaling by ERBB2 TMD/JMD mutants / Constitutive Signaling by EGFRvIII / Downregulation of ERBB2 signaling / cell-cell adhesion / Signaling by ERBB2 ECD mutants / receptor protein-tyrosine kinase / Signaling by ERBB2 KD Mutants / negative regulation of protein catabolic process / positive regulation of miRNA transcription / kinase binding / ruffle membrane / epidermal growth factor receptor signaling pathway / positive regulation of protein phosphorylation / cell morphogenesis / neuron differentiation / positive regulation of fibroblast proliferation / HCMV Early Events / Constitutive Signaling by Aberrant PI3K in Cancer / actin filament binding / Cargo recognition for clathrin-mediated endocytosis / cell junction / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / transmembrane signaling receptor activity / positive regulation of canonical Wnt signaling pathway / Clathrin-mediated endocytosis / PIP3 activates AKT signaling / ATPase binding / virus receptor activity / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / RAF/MAP kinase cascade / positive regulation of cell growth / double-stranded DNA binding / protein tyrosine kinase activity / early endosome membrane / protein phosphatase binding / nuclear membrane / basolateral plasma membrane / learning or memory / Extra-nuclear estrogen signaling / cell surface receptor signaling pathway / 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 / 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
~{N}-(1-methylbenzimidazol-4-yl)prop-2-enamide / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.2 Å
AuthorsDokurno, P.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Rsc Med Chem / Year: 2023
Title: A covalent fragment-based strategy targeting a novel cysteine to inhibit activity of mutant EGFR kinase.
Authors: Kuki, N. / Walmsley, D.L. / Kanai, K. / Takechi, S. / Yoshida, M. / Murakami, R. / Takano, K. / Tominaga, Y. / Takahashi, M. / Ito, S. / Nakao, N. / Angove, H. / Baker, L.M. / Carter, E. / ...Authors: Kuki, N. / Walmsley, D.L. / Kanai, K. / Takechi, S. / Yoshida, M. / Murakami, R. / Takano, K. / Tominaga, Y. / Takahashi, M. / Ito, S. / Nakao, N. / Angove, H. / Baker, L.M. / Carter, E. / Dokurno, P. / Le Strat, L. / Macias, A.T. / Molyneaux, C.A. / Murray, J.B. / Surgenor, A.E. / Hamada, T. / Hubbard, R.E.
History
DepositionDec 26, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Dec 13, 2023Provider: repository / Type: Initial release
Revision 1.1Apr 3, 2024Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation_author.identifier_ORCID / _citation_author.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,1493
Polymers37,5491
Non-polymers6002
Water1,946108
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)144.687, 144.687, 144.687
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number197
Space group name H-MI23
Components on special symmetry positions
IDModelComponents
11A-1306-

HOH

21A-1307-

HOH

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Components

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


Mass: 37549.398 Da / Num. of mol.: 1 / Mutation: T790M, L858R, E865A, E866A, K867A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EGFR, ERBB, ERBB1, HER1 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P00533, receptor protein-tyrosine kinase
#2: Chemical ChemComp-PE5 / 3,6,9,12,15,18,21,24-OCTAOXAHEXACOSAN-1-OL / 2-(2-{2-[2-(2-{2-[2-(2-ETHOXY-ETHOXY)-ETHOXY]-ETHOXY}-ETHOXY)-ETHOXY]-ETHOXY}-ETHOXY)-ETHANOL / POLYETHYLENE GLYCOL PEG400


Mass: 398.489 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H38O9 / Comment: precipitant*YM
#3: Chemical ChemComp-N7C / ~{N}-(1-methylbenzimidazol-4-yl)prop-2-enamide


Mass: 201.225 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C11H11N3O / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 108 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 3.36 Å3/Da / Density % sol: 63.4 %
Crystal growTemperature: 292 K / Method: vapor diffusion, hanging drop / pH: 8.5 / Details: 0.1M TRIS pH 8.5, 0.15M Sodium citrate, 25%PEG400

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SOLEIL / Beamline: PROXIMA 1 / Wavelength: 0.9786 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Aug 15, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9786 Å / Relative weight: 1
ReflectionResolution: 2.06→45.75 Å / Num. obs: 30952 / % possible obs: 99.5 % / Redundancy: 13.8 % / CC1/2: 1 / Rmerge(I) obs: 0.057 / Rpim(I) all: 0.016 / Rrim(I) all: 0.059 / Χ2: 0.92 / Net I/σ(I): 22.7 / Num. measured all: 427473
Reflection shellResolution: 2.06→2.12 Å / % possible obs: 98.3 % / Redundancy: 13.3 % / Rmerge(I) obs: 1.458 / Num. measured all: 29962 / Num. unique obs: 2257 / CC1/2: 0.72 / Rpim(I) all: 0.409 / Rrim(I) all: 1.515 / Χ2: 0.75 / Net I/σ(I) obs: 1.7

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Processing

Software
NameVersionClassification
REFMAC5.8.0238refinement
Aimlessdata scaling
XDSdata reduction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5EDQ

5edq


Resolution: 2.2→20 Å / Cor.coef. Fo:Fc: 0.963 / Cor.coef. Fo:Fc free: 0.949 / SU B: 4.383 / SU ML: 0.111 / Cross valid method: THROUGHOUT / ESU R: 0.177 / ESU R Free: 0.163 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.22445 1310 5.1 %RANDOM
Rwork0.18577 ---
obs0.18778 24229 99.37 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 57.309 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å20 Å20 Å2
2--0 Å20 Å2
3---0 Å2
Refinement stepCycle: 1 / Resolution: 2.2→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2394 0 41 108 2543
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0132490
X-RAY DIFFRACTIONr_bond_other_d0.0010.0172380
X-RAY DIFFRACTIONr_angle_refined_deg1.5741.6483371
X-RAY DIFFRACTIONr_angle_other_deg1.3731.5815507
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.6565305
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.28322.087115
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.76615428
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.9791515
X-RAY DIFFRACTIONr_chiral_restr0.080.2326
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.022708
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02498
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it6.1836.1141223
X-RAY DIFFRACTIONr_mcbond_other6.1876.1121222
X-RAY DIFFRACTIONr_mcangle_it8.4789.1161524
X-RAY DIFFRACTIONr_mcangle_other8.4769.1181525
X-RAY DIFFRACTIONr_scbond_it6.616.2491267
X-RAY DIFFRACTIONr_scbond_other6.6086.2511268
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other9.189.2081847
X-RAY DIFFRACTIONr_long_range_B_refined13.17810241
X-RAY DIFFRACTIONr_long_range_B_other13.17810242
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.2→2.317 Å / Total num. of bins used: 10
RfactorNum. reflection% reflection
Rfree0.303 186 -
Rwork0.244 3448 -
obs--100 %

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