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- PDB-4i22: Structure of the monomeric (V948R)gefitinib/erlotinib resistant d... -

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Basic information

Entry
Database: PDB / ID: 4i22
TitleStructure of the monomeric (V948R)gefitinib/erlotinib resistant double mutant (L858R+T790M) EGFR kinase domain co-crystallized with gefitinib
ComponentsEpidermal growth factor receptor
KeywordsTRANSFERASE / Kinase domain / Phosphotrasfer / ATP binding
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 / regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / ERBB2-EGFR signaling pathway / PTK6 promotes HIF1A stabilization / digestive tract morphogenesis / morphogenesis of an epithelial fold / ERBB2 Activates PTK6 Signaling / intracellular vesicle / Signaling by EGFR / transmembrane receptor protein tyrosine kinase activator activity / negative regulation of epidermal growth factor receptor signaling pathway / protein tyrosine kinase activator activity / response to cobalamin / Signaling by ERBB4 / eyelid development in camera-type eye / protein insertion into membrane / cerebral cortex cell migration / ERBB2 Regulates Cell Motility / regulation of JNK cascade / Respiratory syncytial virus (RSV) attachment and entry / 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 vasoconstriction / positive regulation of glial cell proliferation / 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 / lung development / EGFR downregulation / Signaling by ERBB2 TMD/JMD mutants / 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 / cell-cell adhesion / peptidyl-tyrosine phosphorylation / 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
Gefitinib / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.71 Å
AuthorsGajiwala, K.S. / Feng, J. / Ferre, R. / Ryan, K. / Brodsky, O. / Stewart, A.
CitationJournal: Structure / Year: 2013
Title: Insights into the Aberrant Activity of Mutant EGFR Kinase Domain and Drug Recognition.
Authors: Gajiwala, K.S. / Feng, J. / Ferre, R. / Ryan, K. / Brodsky, O. / Weinrich, S. / Kath, J.C. / Stewart, A.
History
DepositionNov 21, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 16, 2013Provider: repository / Type: Initial release
Revision 1.1Feb 27, 2013Group: Database references
Revision 1.2Oct 15, 2014Group: Non-polymer description
Revision 1.3Nov 15, 2017Group: Refinement description / Category: software / Item: _software.name
Revision 1.4Feb 28, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / software / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _software.name / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.5Mar 27, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond
Item: _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_1 ..._chem_comp_atom.atom_id / _chem_comp_bond.atom_id_1 / _chem_comp_bond.atom_id_2 / _chem_comp_bond.pdbx_aromatic_flag / _chem_comp_bond.pdbx_stereo_config / _chem_comp_bond.value_order

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,2194
Polymers37,5801
Non-polymers6393
Water2,414134
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
A: Epidermal growth factor receptor
hetero molecules

A: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)76,4398
Polymers75,1612
Non-polymers1,2786
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_555-x,y,-z1
Buried area5300 Å2
ΔGint-82 kcal/mol
Surface area26440 Å2
MethodPISA
Unit cell
Length a, b, c (Å)76.519, 35.486, 77.781
Angle α, β, γ (deg.)90.00, 112.89, 90.00
Int Tables number3
Space group name H-MP121

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Components

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


Mass: 37580.453 Da / Num. of mol.: 1 / Fragment: UNP residues 695-1022, EGFR kinase domain / Mutation: T790M, L858R, V948R
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-IRE / Gefitinib


Mass: 446.902 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H24ClFN4O3 / Comment: medication, inhibitor*YM
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 134 / Source method: isolated from a natural source / Formula: H2O

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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: 2.59 Å3/Da / Density % sol: 52.49 %
Crystal growTemperature: 294 K / Method: vapor diffusion, hanging drop / pH: 5.5
Details: 25.0% PEG 3350, 0.2 M Li Sulfate, 0.1 M Bis-Tris pH 5.50, VAPOR DIFFUSION, HANGING DROP, temperature 294K

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Data collection

DiffractionMean temperature: 98 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: Aug 18, 2011 / Details: Mirrors
RadiationMonochromator: 1 / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.71→42.64 Å / Num. all: 41633 / Num. obs: 39302 / % possible obs: 94.4 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 3.2 % / Biso Wilson estimate: 26.5 Å2 / Rmerge(I) obs: 0.028 / Net I/σ(I): 19.9
Reflection shellResolution: 1.71→1.81 Å / Redundancy: 2.7 % / Rmerge(I) obs: 0.342 / Mean I/σ(I) obs: 2.5 / Num. unique all: 4780 / % possible all: 79.3

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Processing

Software
NameClassification
JDirectordata collection
CNXrefinement
autoPROCdata scaling
SCALAdata scaling
CNXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.71→42.64 Å / Rfactor Rfree error: 0.005 / Data cutoff high absF: 927519.3 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.224 1980 5 %RANDOM
Rwork0.197 ---
all0.198 39296 --
obs0.198 39296 93.1 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 42.311 Å2 / ksol: 0.37268 e/Å3
Displacement parametersBiso mean: 31.9 Å2
Baniso -1Baniso -2Baniso -3
1--1.66 Å20 Å20.81 Å2
2--3.37 Å20 Å2
3----1.71 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.24 Å0.2 Å
Luzzati d res low-5 Å
Luzzati sigma a0.2 Å0.15 Å
Refinement stepCycle: LAST / Resolution: 1.71→42.64 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2400 0 41 134 2575
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.004
X-RAY DIFFRACTIONc_angle_deg0.8
X-RAY DIFFRACTIONc_dihedral_angle_d18.8
X-RAY DIFFRACTIONc_improper_angle_d0.62
X-RAY DIFFRACTIONc_mcbond_it1.431.5
X-RAY DIFFRACTIONc_mcangle_it2.32
X-RAY DIFFRACTIONc_scbond_it2.142
X-RAY DIFFRACTIONc_scangle_it3.322.5
Refine LS restraints NCSNCS model details: NONE
LS refinement shellResolution: 1.71→1.82 Å / Rfactor Rfree error: 0.022 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.356 250 4.7 %
Rwork0.282 5109 -
obs--77.3 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1protein_rep.paraprotein.top
X-RAY DIFFRACTION2dna-rna_rep.paradna-rna.top
X-RAY DIFFRACTION3water_rep.paramwater.top
X-RAY DIFFRACTION4ion.paramion.top
X-RAY DIFFRACTION5lig.paramlig.top

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