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- PDB-9h46: EGFR wild type in complex with 25328 -

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Basic information

Entry
Database: PDB / ID: 9h46
TitleEGFR wild type in complex with 25328
ComponentsEpidermal growth factor receptor
KeywordsTRANSFERASE / KINASE / EGFR / INHIBITOR
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 / EGFR interacts with phospholipase C-gamma / epidermal growth factor receptor activity / 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 / EGFR interacts with phospholipase C-gamma / epidermal growth factor receptor activity / 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 / eyelid development in camera-type eye / negative regulation of epidermal growth factor receptor signaling pathway / 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 / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / SHC1 events in EGFR signaling / transmembrane receptor protein tyrosine kinase activity / EGFR Transactivation by Gastrin / 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 / Signal transduction by L1 / positive regulation of epithelial cell proliferation / 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 / receptor protein-tyrosine kinase / negative regulation of protein catabolic process / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / positive regulation of miRNA transcription / kinase binding / ruffle membrane / positive regulation of protein phosphorylation / epidermal growth factor receptor signaling pathway / neuron differentiation / cell morphogenesis / 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 / transmembrane signaling receptor activity / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / positive regulation of canonical Wnt signaling pathway / Clathrin-mediated endocytosis / PIP3 activates AKT signaling / virus receptor activity / ATPase binding / RAF/MAP kinase cascade / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / 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
: / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.163 Å
AuthorsPintar, S. / Martin, M.P. / Noble, M.E.M.
Funding support United Kingdom, 2items
OrganizationGrant numberCountry
Cancer Research UKDRCDDRPGMApr2020100002 United Kingdom
Medical Research Council (MRC, United Kingdom)MR/X004872/1 United Kingdom
CitationJournal: To Be Published
Title: Covalent alkynylpyridopyrimidinones targeting cysteine 775 of the epidermal growth factor receptor overcome resistance to current therapies
Authors: Stewart, H.L. / Waring, M.J.
History
DepositionOct 17, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 4, 2024Provider: repository / Type: Initial release

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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)37,8082
Polymers37,4351
Non-polymers3721
Water55831
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration, monomer
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area720 Å2
ΔGint-1 kcal/mol
Surface area14890 Å2
MethodPISA
Unit cell
Length a, b, c (Å)144.696, 144.696, 144.696
Angle α, β, γ (deg.)90, 90, 90
Int Tables number197
Space group name H-MI23

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Components

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


Mass: 37435.328 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EGFR, ERBB, ERBB1, HER1 / Production host: Escherichia coli (E. coli)
References: UniProt: P00533, receptor protein-tyrosine kinase
#2: Chemical ChemComp-A1ISA / 5-ethyl-2-[(2-methoxyphenyl)amino]-8-phenyl-pyrido[2,3-d]pyrimidin-7-one


Mass: 372.420 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H20N4O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 31 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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: 3.37 Å3/Da / Density % sol: 63.52 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.6
Details: 25 mM HEPES pH 8, 150 mM NaCl, 10 % glycerol, 1 mM DTT 85mM Tris pH 7.6, 140 mM acetate, 23.5 % Polyethylene glycol 4,000, 18% glycerol
PH range: 7.5-8.5

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Data collection

DiffractionMean temperature: 173 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.92 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Dec 5, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.92 Å / Relative weight: 1
ReflectionResolution: 3.16→45.799 Å / Num. obs: 8781 / % possible obs: 100 % / Redundancy: 1.9 % / CC1/2: 1 / Rmerge(I) obs: 0.029 / Net I/σ(I): 15
Reflection shellResolution: 3.16→3.38 Å / Rmerge(I) obs: 0.4 / Mean I/σ(I) obs: 1.7 / Num. unique obs: 1580 / CC1/2: 0.712

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Processing

Software
NameVersionClassification
REFMAC5.8.0430 (refmacat 0.4.82)refinement
xia2data reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 3.163→45.799 Å / Cor.coef. Fo:Fc: 0.948 / Cor.coef. Fo:Fc free: 0.94 / SU B: 21.866 / SU ML: 0.356 / Cross valid method: FREE R-VALUE / ESU R Free: 0.444
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2564 432 4.92 %
Rwork0.2125 8349 -
all0.214 --
obs-8781 99.954 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT
Displacement parametersBiso mean: 115.876 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å20 Å20 Å2
2--0 Å20 Å2
3---0 Å2
Refinement stepCycle: LAST / Resolution: 3.163→45.799 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2363 0 28 31 2422
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0122444
X-RAY DIFFRACTIONr_bond_other_d0.0010.0162323
X-RAY DIFFRACTIONr_angle_refined_deg1.3431.8193318
X-RAY DIFFRACTIONr_angle_other_deg0.4641.7575366
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.3725302
X-RAY DIFFRACTIONr_dihedral_angle_2_deg22.8436.38918
X-RAY DIFFRACTIONr_dihedral_angle_3_deg24.61510418
X-RAY DIFFRACTIONr_dihedral_angle_6_deg16.3651096
X-RAY DIFFRACTIONr_chiral_restr0.0540.2377
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.022820
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02520
X-RAY DIFFRACTIONr_nbd_refined0.2390.2610
X-RAY DIFFRACTIONr_symmetry_nbd_other0.2310.22429
X-RAY DIFFRACTIONr_nbtor_refined0.1940.21210
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0920.21429
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.2620.263
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_other0.0390.22
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.2580.215
X-RAY DIFFRACTIONr_nbd_other0.210.263
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.2770.22
X-RAY DIFFRACTIONr_mcbond_it9.00711.5631217
X-RAY DIFFRACTIONr_mcbond_other8.98211.5651217
X-RAY DIFFRACTIONr_mcangle_it12.63320.8521516
X-RAY DIFFRACTIONr_mcangle_other12.63220.8551517
X-RAY DIFFRACTIONr_scbond_it9.29311.7971227
X-RAY DIFFRACTIONr_scbond_other9.2911.7971228
X-RAY DIFFRACTIONr_scangle_it13.50821.5361802
X-RAY DIFFRACTIONr_scangle_other13.50421.5381803
X-RAY DIFFRACTIONr_lrange_it18.769138.89910284
X-RAY DIFFRACTIONr_lrange_other18.768138.89810285
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 20 / % reflection obs: 100 %

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRfactor allNum. reflection allFsc freeFsc workWRfactor Rwork
3.163-3.2450.314370.3026050.3036420.9210.9260.303
3.245-3.3340.251390.3075880.3036270.9440.9310.301
3.334-3.430.279310.2755740.2756050.9590.9460.261
3.43-3.5350.307370.265480.2635850.9240.9510.239
3.535-3.650.306260.2335460.2375720.940.9640.21
3.65-3.7770.244370.2215000.2235370.9540.9690.197
3.777-3.9190.252210.2215330.2225540.9560.9680.197
3.919-4.0770.214260.1944780.1955040.9440.9750.177
4.077-4.2570.3190.1944730.1974920.940.9750.176
4.257-4.4630.197250.1834460.1844710.980.9770.164
4.463-4.7020.181140.1734500.1744640.9740.9790.163
4.702-4.9840.214170.1934090.1944260.9710.9760.181
4.984-5.3240.262230.1863740.1893970.9470.9770.172
5.324-5.7440.462160.2373620.2473780.8990.9560.223
5.744-6.2820.277170.2333330.2353500.9230.9630.215
6.282-7.0070.412170.2333020.2413190.9150.9620.235
7.007-8.060.195100.2092790.2082890.9790.9720.223
8.06-9.7950.155110.1672300.1662410.9910.9840.198
9.795-13.5460.24270.1641920.1661990.9810.9850.191
13.546-45.7990.35520.3331270.33412910.9240.401

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