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- PDB-3ika: Crystal Structure of EGFR 696-1022 T790M Mutant Covalently Bindin... -

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Basic information

Entry
Database: PDB / ID: 3ika
TitleCrystal Structure of EGFR 696-1022 T790M Mutant Covalently Binding to WZ4002
ComponentsEpidermal growth factor receptor
KeywordsTRANSFERASE / EGFR / T790M / WZ4002 / WZ-4002 / Alternative splicing / ATP-binding / Cell membrane / Disease mutation / Disulfide bond / Glycoprotein / Isopeptide bond / Kinase / Membrane / Nucleotide-binding / Phosphoprotein / Polymorphism / Receptor / Secreted / Transmembrane / Tumor suppressor / Tyrosine-protein kinase / Ubl conjugation
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 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); 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-0UN / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.9 Å
AuthorsYun, C.-H. / Eck, M.J.
CitationJournal: Nature / Year: 2009
Title: Novel mutant-selective EGFR kinase inhibitors against EGFR T790M.
Authors: Zhou, W. / Ercan, D. / Chen, L. / Yun, C.H. / Li, D. / Capelletti, M. / Cortot, A.B. / Chirieac, L. / Iacob, R.E. / Padera, R. / Engen, J.R. / Wong, K.K. / Eck, M.J. / Gray, N.S. / Janne, P.A.
History
DepositionAug 5, 2009Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 12, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Oct 13, 2021Group: Database references / Derived calculations
Category: database_2 / struct_conn ...database_2 / struct_conn / 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 / _struct_conn.pdbx_leaving_atom_flag / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.3Nov 27, 2024Group: Data collection / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / pdbx_entry_details / pdbx_modification_feature

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)75,8203
Polymers75,3252
Non-polymers4951
Water2,666148
1
A: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,1582
Polymers37,6631
Non-polymers4951
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Epidermal growth factor receptor


Theoretical massNumber of molelcules
Total (without water)37,6631
Polymers37,6631
Non-polymers00
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2000 Å2
ΔGint-14 kcal/mol
Surface area28360 Å2
MethodPISA
Unit cell
Length a, b, c (Å)48.230, 89.126, 165.224
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Epidermal growth factor receptor / Receptor tyrosine-protein kinase ErbB-1


Mass: 37662.543 Da / Num. of mol.: 2 / Fragment: 694-1022 / Mutation: T790M
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EGFR, ERBB1 / Plasmid: pAcG2T / Production host: Spodoptera frugiperda (fall armyworm) / Strain (production host): sf9
References: UniProt: P00533, receptor protein-tyrosine kinase
#2: Chemical ChemComp-0UN / N-{3-[(5-chloro-2-{[2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino}pyrimidin-4-yl)oxy]phenyl}prop-2-enamide


Mass: 494.973 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H27ClN6O3
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 148 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 2

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Sample preparation

CrystalDensity Matthews: 2.36 Å3/Da / Density % sol: 47.82 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.4
Details: 0.1M Hepes 7.4, 22% PEG6000, 0.3M NaCl, 5mM TCEP, VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

Diffraction
IDMean temperature (K)Crystal-ID
11001
21001
Diffraction source
SourceSiteBeamlineIDWavelength (Å)
SYNCHROTRONAPS 24-ID-E10.97918
SYNCHROTRONAPS 24-ID-E20.97918
Detector
TypeIDDetectorDate
ADSC QUANTUM 3151CCDFeb 4, 2009
ADSC QUANTUM 3152CCDJun 10, 2009
Radiation
IDProtocolMonochromatic (M) / Laue (L)Scattering typeWavelength-ID
1SINGLE WAVELENGTHMx-ray1
2SINGLE WAVELENGTHMx-ray1
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
ReflectionResolution: 2.9→21 Å / Num. all: 16634 / Num. obs: 16329 / % possible obs: 96.4 % / Observed criterion σ(I): -0.7 / Redundancy: 4 % / Biso Wilson estimate: 95.7 Å2 / Rmerge(I) obs: 0.132 / Net I/σ(I): 9.3
Reflection shellResolution: 2.9→3.12 Å / Redundancy: 2.7 % / Rmerge(I) obs: 0.399 / Mean I/σ(I) obs: 2.6 / % possible all: 89

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Processing

Software
NameVersionClassification
ADSCQuantumdata collection
PHASERphasing
REFMAC5.5.0093refinement
DENZOdata reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.9→20.83 Å / Cor.coef. Fo:Fc: 0.938 / Cor.coef. Fo:Fc free: 0.904 / Cross valid method: THROUGHOUT / ESU R Free: 0.445 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.25706 806 5.1 %RANDOM
Rwork0.20798 ---
all0.21029 15136 --
obs0.21029 15136 97.03 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 62.121 Å2
Baniso -1Baniso -2Baniso -3
1-3.76 Å20 Å20 Å2
2--1.76 Å20 Å2
3----5.52 Å2
Refinement stepCycle: LAST / Resolution: 2.9→20.83 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4921 0 35 148 5104
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0250.0225062
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.7321.9826845
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.5885616
X-RAY DIFFRACTIONr_dihedral_angle_2_deg40.49524.225213
X-RAY DIFFRACTIONr_dihedral_angle_3_deg23.34715924
X-RAY DIFFRACTIONr_dihedral_angle_4_deg26.2351529
X-RAY DIFFRACTIONr_chiral_restr0.1190.2761
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.0213735
X-RAY DIFFRACTIONr_gen_planes_other
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_it1.2671.53091
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it2.33924996
X-RAY DIFFRACTIONr_scbond_it1.77231971
X-RAY DIFFRACTIONr_scangle_it2.9094.51848
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.9→2.974 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.394 61 -
Rwork0.319 975 -
obs--86.48 %

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