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- PDB-4zse: Crystal structure of EGFR 696-1022 T790M/V948R, crystal form II -

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Basic information

Entry
Database: PDB / ID: 4zse
TitleCrystal structure of EGFR 696-1022 T790M/V948R, crystal form II
ComponentsEpidermal growth factor receptor
KeywordsTRANSFERASE / EGFR / T790M / V948R
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 / regulation of nitric-oxide synthase activity / morphogenesis of an epithelial fold / ERBB2 Activates PTK6 Signaling / intracellular vesicle / Signaling by EGFR / response to cobalamin / negative regulation of epidermal growth factor receptor signaling pathway / transmembrane receptor protein tyrosine kinase activator activity / protein tyrosine kinase activator activity / regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / Signaling by ERBB4 / protein insertion into membrane / eyelid development in camera-type eye / cerebral cortex cell migration / ERBB2 Regulates Cell Motility / regulation of JNK cascade / activation of phospholipase C activity / positive regulation of cyclin-dependent protein serine/threonine kinase activity / PI3K events in ERBB2 signaling / negative regulation of mitotic cell cycle / hair follicle development / MAP kinase kinase kinase activity / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / positive regulation of G1/S transition of mitotic cell cycle / embryonic placenta development / positive regulation of bone resorption / positive regulation of DNA replication / GAB1 signalosome / positive regulation of nitric oxide mediated signal transduction / salivary gland morphogenesis / regulation of peptidyl-tyrosine phosphorylation / peptidyl-tyrosine autophosphorylation / positive regulation of phosphorylation / positive regulation of glial cell proliferation / positive regulation of vasoconstriction / Signaling by ERBB2 / cellular response to epidermal growth factor stimulus / cellular response to cadmium ion / positive regulation of DNA repair / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / GRB2 events in ERBB2 signaling / neurogenesis / transmembrane receptor protein tyrosine kinase activity / cellular response to dexamethasone stimulus / SHC1 events in ERBB2 signaling / ossification / positive regulation of synaptic transmission, glutamatergic / basal plasma membrane / regulation of ERK1 and ERK2 cascade / neuron projection morphogenesis / positive regulation of superoxide anion generation / Signal transduction by L1 / epithelial cell proliferation / cellular response to estradiol stimulus / liver regeneration / NOTCH3 Activation and Transmission of Signal to the Nucleus / positive regulation of epithelial cell proliferation / astrocyte activation / cellular response to amino acid stimulus / positive regulation of protein localization to plasma membrane / EGFR downregulation / lung development / clathrin-coated endocytic vesicle membrane / positive regulation of smooth muscle cell proliferation / Signaling by ERBB2 TMD/JMD mutants / Constitutive Signaling by EGFRvIII / positive regulation of MAP kinase activity / Signaling by ERBB2 ECD mutants / epidermal growth factor receptor signaling pathway / Signaling by ERBB2 KD Mutants / negative regulation of protein catabolic process / cell-cell adhesion / receptor protein-tyrosine kinase / ruffle membrane / Downregulation of ERBB2 signaling / kinase binding
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 / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / 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
PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.97 Å
AuthorsYan, X.E. / Yun, C.H.
Funding support China, 1items
OrganizationGrant numberCountry
China
CitationJournal: To Be Published
Title: Ibrutinib Selectively and Irreversibly Targets EGFR-mutant non-Small Cell Lung Cancer Cells
Authors: Wu, H. / Wang, A. / Zhang, W. / Wang, B. / Wang, B. / Yan, X.E. / Chen, C. / Hu, C. / Ye, Z. / Zhao, Z. / Wang, L. / Li, X. / Yu, K. / Liu, J. / Wu, J. / Wang, J. / Wang, C. / Weisberg, E.L. ...Authors: Wu, H. / Wang, A. / Zhang, W. / Wang, B. / Wang, B. / Yan, X.E. / Chen, C. / Hu, C. / Ye, Z. / Zhao, Z. / Wang, L. / Li, X. / Yu, K. / Liu, J. / Wu, J. / Wang, J. / Wang, C. / Weisberg, E.L. / Liu, J. / Gray, N.S. / Chen, L. / Yun, C.H. / Liu, Q.
History
DepositionMay 13, 2015Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Jun 15, 2016Provider: repository / Type: Initial release
Revision 1.1Nov 8, 2023Group: 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 / pdbx_initial_refinement_model / pdbx_prerelease_seq / pdbx_struct_oper_list / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_oper_list.symmetry_operation / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)153,08213
Polymers150,8984
Non-polymers2,1849
Water14,376798
1
A: Epidermal growth factor receptor
D: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)76,5106
Polymers75,4492
Non-polymers1,0614
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5030 Å2
ΔGint-45 kcal/mol
Surface area25490 Å2
MethodPISA
2
B: Epidermal growth factor receptor
C: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)76,5727
Polymers75,4492
Non-polymers1,1235
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6100 Å2
ΔGint-43 kcal/mol
Surface area26440 Å2
MethodPISA
Unit cell
Length a, b, c (Å)71.820, 102.317, 86.752
Angle α, β, γ (deg.)90.00, 101.24, 90.00
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: 37724.598 Da / Num. of mol.: 4 / Fragment: UNP RESIDUES 695-1022 / Mutation: T790M, V948R
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EGFR, ERBB, ERBB1, HER1 / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P00533, receptor protein-tyrosine kinase
#2: Chemical
ChemComp-ANP / PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER


Mass: 506.196 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C10H17N6O12P3 / Comment: AMP-PNP, energy-carrying molecule analogue*YM
#3: Chemical
ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 798 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.1 Å3/Da / Density % sol: 41.47 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 6 / Details: 25% PEG 3350, 100mM Bis-Tris pH 6.0

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: BRUKER AXS MICROSTAR / Wavelength: 1.5418 Å
DetectorType: MAR scanner 345 mm plate / Detector: IMAGE PLATE / Date: Jul 28, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.97→50 Å / Num. obs: 82387 / % possible obs: 94.3 % / Redundancy: 2.4 % / Rmerge(I) obs: 0.052 / Net I/σ(I): 15.9
Reflection shellResolution: 1.97→2.02 Å / Redundancy: 2.3 % / Rmerge(I) obs: 0.325 / Mean I/σ(I) obs: 2 / % possible all: 88.9

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Processing

Software
NameVersionClassification
PHENIX1.8.4_1496refinement
PHASERphasing
HKL-3000data processing
Cootmodel building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4ZQJ

4zqj
PDB Unreleased entry


Resolution: 1.97→23.859 Å / SU ML: 0.21 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 22.15 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2126 4120 5 %
Rwork0.1902 --
obs0.1913 82368 93.82 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.97→23.859 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9610 0 132 798 10540
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01510011
X-RAY DIFFRACTIONf_angle_d1.37813591
X-RAY DIFFRACTIONf_dihedral_angle_d18.1583806
X-RAY DIFFRACTIONf_chiral_restr0.1221536
X-RAY DIFFRACTIONf_plane_restr0.011691
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.9629-1.9860.32961050.29642187X-RAY DIFFRACTION75
1.986-2.01020.26661290.26992565X-RAY DIFFRACTION90
2.0102-2.03560.27311480.2582567X-RAY DIFFRACTION91
2.0356-2.06240.28111410.24012706X-RAY DIFFRACTION93
2.0624-2.09060.27921680.23972583X-RAY DIFFRACTION92
2.0906-2.12050.28221640.22852682X-RAY DIFFRACTION93
2.1205-2.15210.25691330.21982657X-RAY DIFFRACTION93
2.1521-2.18570.25531460.2212658X-RAY DIFFRACTION93
2.1857-2.22150.25431250.21392677X-RAY DIFFRACTION93
2.2215-2.25980.23541200.21692708X-RAY DIFFRACTION94
2.2598-2.30090.24431270.21762704X-RAY DIFFRACTION94
2.3009-2.34510.25571480.21352705X-RAY DIFFRACTION94
2.3451-2.39290.25261360.21822740X-RAY DIFFRACTION94
2.3929-2.44490.24711560.21092674X-RAY DIFFRACTION94
2.4449-2.50170.21771370.21242724X-RAY DIFFRACTION95
2.5017-2.56420.23481480.20612742X-RAY DIFFRACTION95
2.5642-2.63340.21811590.20592709X-RAY DIFFRACTION95
2.6334-2.71080.24271680.20462720X-RAY DIFFRACTION96
2.7108-2.79820.25481300.20672766X-RAY DIFFRACTION96
2.7982-2.8980.25591300.21022759X-RAY DIFFRACTION96
2.898-3.01380.26361330.19442796X-RAY DIFFRACTION96
3.0138-3.15070.21731640.19632749X-RAY DIFFRACTION97
3.1507-3.31640.2031390.18472789X-RAY DIFFRACTION97
3.3164-3.52360.19571280.16852807X-RAY DIFFRACTION97
3.5236-3.79470.16671490.15652831X-RAY DIFFRACTION97
3.7947-4.17470.17831580.1532784X-RAY DIFFRACTION97
4.1747-4.77460.15581350.14612810X-RAY DIFFRACTION96
4.7746-5.99960.17061480.1742774X-RAY DIFFRACTION96
5.9996-23.86050.16931480.1772675X-RAY DIFFRACTION91

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