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- PDB-6v66: EGFR(T790M/V948R) in complex with LN2899 -

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Basic information

Entry
Database: PDB / ID: 6v66
TitleEGFR(T790M/V948R) in complex with LN2899
ComponentsEpidermal growth factor receptor
KeywordsTRANSFERASE/TRANSFERASE inhibitor / egfr / inhibitor / TRANSFERASE-TRANSFERASE inhibitor complex
Function / homology
Function and homology information


response to hydroxyisoflavone / multivesicular body, internal vesicle lumen / positive regulation of protein kinase C activity / positive regulation of prolactin secretion / negative regulation of cardiocyte differentiation / 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 protein kinase C activity / positive regulation of prolactin secretion / negative regulation of cardiocyte differentiation / 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 / epidermal growth factor binding / response to UV-A / tongue development / PLCG1 events in ERBB2 signaling / midgut development / hydrogen peroxide metabolic process / ERBB2-EGFR signaling pathway / regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / PTK6 promotes HIF1A stabilization / digestive tract morphogenesis / morphogenesis of an epithelial fold / ERBB2 Activates PTK6 Signaling / intracellular vesicle / Signaling by EGFR / protein tyrosine kinase activator activity / transmembrane receptor protein tyrosine kinase activator activity / negative regulation of epidermal growth factor receptor signaling pathway / response to cobalamin / Signaling by ERBB4 / eyelid development in camera-type eye / 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 / MAP kinase kinase kinase activity / hair follicle development / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / embryonic placenta development / positive regulation of bone resorption / GAB1 signalosome / positive regulation of G1/S transition of mitotic cell cycle / salivary gland morphogenesis / peptidyl-tyrosine autophosphorylation / positive regulation of phosphorylation / regulation of peptidyl-tyrosine phosphorylation / positive regulation of glial cell proliferation / positive regulation of vasoconstriction / Signaling by ERBB2 / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / cellular response to epidermal growth factor stimulus / cellular response to cadmium ion / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / GRB2 events in ERBB2 signaling / transmembrane receptor protein tyrosine kinase activity / positive regulation of DNA repair / regulation of ERK1 and ERK2 cascade / SHC1 events in ERBB2 signaling / ossification / cellular response to dexamethasone stimulus / neurogenesis / positive regulation of synaptic transmission, glutamatergic / positive regulation of epithelial cell proliferation / neuron projection morphogenesis / basal plasma membrane / epithelial cell proliferation / positive regulation of superoxide anion generation / positive regulation of DNA replication / Signal transduction by L1 / cellular response to estradiol stimulus / NOTCH3 Activation and Transmission of Signal to the Nucleus / astrocyte activation / liver regeneration / cellular response to amino acid stimulus / positive regulation of protein localization to plasma membrane / Signaling by ERBB2 TMD/JMD mutants / lung development / EGFR downregulation / positive regulation of smooth muscle cell proliferation / positive regulation of MAP kinase activity / Constitutive Signaling by EGFRvIII / clathrin-coated endocytic vesicle membrane / Signaling by ERBB2 ECD mutants / epidermal growth factor receptor signaling pathway / Signaling by ERBB2 KD Mutants / receptor protein-tyrosine kinase / negative regulation of protein catabolic process / kinase binding / Downregulation of ERBB2 signaling / positive regulation of miRNA transcription / peptidyl-tyrosine phosphorylation / cell-cell adhesion / ruffle 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 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-QP1 / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.79 Å
AuthorsHeppner, D.E. / Eck, M.J.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)R01CA201049 United States
CitationJournal: J.Med.Chem. / Year: 2020
Title: Structural Basis for EGFR Mutant Inhibition by Trisubstituted Imidazole Inhibitors.
Authors: Heppner, D.E. / Gunther, M. / Wittlinger, F. / Laufer, S.A. / Eck, M.J.
History
DepositionDec 4, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 22, 2020Provider: repository / Type: Initial release
Revision 1.1May 6, 2020Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Feb 23, 2022Group: Database references / Experimental preparation / Category: database_2 / exptl_crystal
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _exptl_crystal.pdbx_mosaicity
Revision 1.3Oct 11, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.4Oct 30, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
D: Epidermal growth factor receptor
A: Epidermal growth factor receptor
B: Epidermal growth factor receptor
C: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)151,92214
Polymers149,5694
Non-polymers2,35210
Water17,799988
1
D: Epidermal growth factor receptor
B: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)76,0238
Polymers74,7852
Non-polymers1,2386
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3700 Å2
ΔGint-40 kcal/mol
Surface area26950 Å2
MethodPISA
2
A: Epidermal growth factor receptor
C: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)75,8996
Polymers74,7852
Non-polymers1,1144
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3420 Å2
ΔGint-44 kcal/mol
Surface area26180 Å2
MethodPISA
Unit cell
Length a, b, c (Å)71.480, 102.448, 87.422
Angle α, β, γ (deg.)90.000, 102.780, 90.000
Int Tables number4
Space group name H-MP1211

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Components

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


Mass: 37392.285 Da / Num. of mol.: 4 / Mutation: T790M,V948R
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EGFR, ERBB, ERBB1, HER1 / Plasmid: pEX / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P00533, receptor protein-tyrosine kinase
#2: Chemical
ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Cl
#3: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6O2
#4: Chemical
ChemComp-QP1 / N-{3-[(4-{4-(4-fluorophenyl)-2-[(2-methoxyethyl)sulfanyl]-1H-imidazol-5-yl}pyridin-2-yl)amino]-4-methoxyphenyl}propanamide


Mass: 521.606 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C27H28FN5O3S / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 988 / 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: 2.08 Å3/Da / Density % sol: 40.93 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 5.5 / Details: 0.1 M Bis-Tris, 25% PEG3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-E / Wavelength: 0.9791 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Jul 18, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9791 Å / Relative weight: 1
ReflectionResolution: 1.79→102.52 Å / Num. obs: 115206 / % possible obs: 99.7 % / Redundancy: 7 % / CC1/2: 0.998 / Rmerge(I) obs: 0.109 / Rpim(I) all: 0.044 / Rrim(I) all: 0.117 / Net I/σ(I): 9.6 / Num. measured all: 802493 / Scaling rejects: 932
Reflection shell

Diffraction-ID: 1 / % possible all: 100

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs
1.79-1.847.10.926021885030.570.3690.9921.9
8.01-102.527.20.039977013530.9990.0160.04229.7

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Processing

Software
NameVersionClassification
PHENIX1.17.1_3660refinement
Aimless0.7.2data scaling
PDB_EXTRACT3.25data extraction
xia2data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5d41

5d41


Resolution: 1.79→85.26 Å / SU ML: 0.24 / Cross valid method: THROUGHOUT / σ(F): 1.39 / Phase error: 24.19 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2261 5744 4.99 %
Rwork0.1853 109415 -
obs0.1873 115159 99.43 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 95.87 Å2 / Biso mean: 29.072 Å2 / Biso min: 10.06 Å2
Refinement stepCycle: final / Resolution: 1.79→85.26 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9884 0 160 988 11032
Biso mean--23.69 35.13 -
Num. residues----1229
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 30

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.79-1.810.34921550.30843376353193
1.81-1.830.32951930.297636863879100
1.83-1.850.33521580.285936513809100
1.85-1.880.30682150.279636313846100
1.88-1.90.33351700.273136913861100
1.9-1.930.29791890.253736613850100
1.93-1.950.29321950.242436403835100
1.95-1.980.29531730.240736803853100
1.98-2.010.2491830.227936283811100
2.01-2.050.26531850.22736873872100
2.05-2.080.23821670.216436393806100
2.08-2.120.2672140.21473617383199
2.12-2.160.25081940.2033586378099
2.16-2.20.25081900.199336543844100
2.2-2.250.2531860.197836613847100
2.25-2.310.22791940.195237033897100
2.31-2.360.24712030.188236253828100
2.36-2.430.26991950.189336483843100
2.43-2.50.24252050.19236733878100
2.5-2.580.24632040.187836203824100
2.58-2.670.2411990.18536513850100
2.67-2.780.22942050.184536823887100
2.78-2.90.22741660.18723651381799
2.9-3.060.25642130.18343593380698
3.06-3.250.19271950.1753661385699
3.25-3.50.22391940.169936763870100
3.5-3.850.18842050.155836613866100
3.85-4.410.17861980.138536713869100
4.41-5.560.18741870.15213713390099
5.56-85.260.17222140.16563699391399

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