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- PDB-5yu9: Crystal structure of EGFR 696-1022 T790M in complex with Ibrutinib -

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Basic information

Entry
Database: PDB / ID: 5yu9
TitleCrystal structure of EGFR 696-1022 T790M in complex with Ibrutinib
ComponentsEpidermal growth factor receptor
KeywordsONCOPROTEIN / EGFR / T790M / ibrutinib / inhibitor
Function / homology
Function and homology information


positive regulation of protein kinase C activity / multivesicular body, internal vesicle lumen / negative regulation of cardiocyte differentiation / response to hydroxyisoflavone / diterpenoid metabolic process / positive regulation of prolactin secretion / Shc-EGFR complex / Inhibition of Signaling by Overexpressed EGFR / ovulation cycle / EGFR interacts with phospholipase C-gamma ...positive regulation of protein kinase C activity / multivesicular body, internal vesicle lumen / negative regulation of cardiocyte differentiation / response to hydroxyisoflavone / diterpenoid metabolic process / positive regulation of prolactin secretion / Shc-EGFR complex / Inhibition of Signaling by Overexpressed EGFR / ovulation cycle / EGFR interacts with phospholipase C-gamma / positive regulation of mucus secretion / regulation of peptidyl-tyrosine phosphorylation / epidermal growth factor binding / tongue development / response to UV-A / PLCG1 events in ERBB2 signaling / midgut development / ERBB2-EGFR signaling pathway / hydrogen peroxide metabolic process / morphogenesis of an epithelial fold / PTK6 promotes HIF1A stabilization / ERBB2 Activates PTK6 Signaling / digestive tract morphogenesis / Signaling by EGFR / response to cobalamin / intracellular vesicle / negative regulation of epidermal growth factor receptor signaling pathway / eyelid development in camera-type eye / cerebral cortex cell migration / protein insertion into membrane / ERBB2 Regulates Cell Motility / protein tyrosine kinase activator activity / Respiratory syncytial virus (RSV) attachment and entry / positive regulation of bone resorption / Signaling by ERBB4 / PI3K events in ERBB2 signaling / negative regulation of mitotic cell cycle / positive regulation of phosphorylation / placental growth factor receptor activity / hepatocyte growth factor receptor activity / boss receptor activity / stem cell factor receptor activity / platelet-derived growth factor beta-receptor activity / brain-derived neurotrophic factor receptor activity / positive regulation of peptidyl-serine phosphorylation / platelet-derived growth factor alpha-receptor activity / epidermal growth factor receptor activity / hair follicle development / macrophage colony-stimulating factor receptor activity / peptidyl-tyrosine autophosphorylation / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / protein tyrosine kinase collagen receptor activity / MAP kinase kinase kinase activity / positive regulation of G1/S transition of mitotic cell cycle / GAB1 signalosome / transmembrane-ephrin receptor activity / insulin-like growth factor receptor activity / embryonic placenta development / vascular endothelial growth factor receptor activity / GPI-linked ephrin receptor activity / salivary gland morphogenesis / positive regulation of vasoconstriction / fibroblast growth factor receptor activity / insulin receptor activity / Signaling by ERBB2 / positive regulation of glial cell proliferation / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / transmembrane receptor protein tyrosine kinase activity / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / cellular response to dexamethasone stimulus / GRB2 events in ERBB2 signaling / positive regulation of synaptic transmission, glutamatergic / SHC1 events in ERBB2 signaling / ossification / basal plasma membrane / positive regulation of DNA repair / cellular response to epidermal growth factor stimulus / positive regulation of epithelial cell proliferation / positive regulation of superoxide anion generation / positive regulation of DNA replication / epithelial cell proliferation / neuron projection morphogenesis / Signal transduction by L1 / positive regulation of smooth muscle cell proliferation / positive regulation of protein localization to plasma membrane / astrocyte activation / liver regeneration / cellular response to amino acid stimulus / NOTCH3 Activation and Transmission of Signal to the Nucleus / cellular response to estradiol stimulus / phosphatidylinositol 3-kinase/protein kinase B signal transduction / lung development / EGFR downregulation / synaptic membrane / clathrin-coated endocytic vesicle membrane / peptidyl-tyrosine phosphorylation / Signaling by ERBB2 TMD/JMD mutants / Constitutive Signaling by EGFRvIII
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-1E8 / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.95 Å
AuthorsYan, X.E. / Yun, C.H.
CitationJournal: Oncotarget / Year: 2016
Title: Ibrutinib targets mutant-EGFR kinase with a distinct binding conformation.
Authors: Wang, A. / Yan, X.E. / Wu, H. / Wang, W. / Hu, C. / Chen, C. / Zhao, Z. / Zhao, P. / Li, X. / Wang, L. / Wang, B. / Ye, Z. / Wang, J. / Wang, C. / Zhang, W. / Gray, N.S. / Weisberg, E.L. / ...Authors: Wang, A. / Yan, X.E. / Wu, H. / Wang, W. / Hu, C. / Chen, C. / Zhao, Z. / Zhao, P. / Li, X. / Wang, L. / Wang, B. / Ye, Z. / Wang, J. / Wang, C. / Zhang, W. / Gray, N.S. / Weisberg, E.L. / Chen, L. / Liu, J. / Yun, C.H. / Liu, Q.
History
DepositionNov 21, 2017Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Dec 27, 2017Provider: repository / Type: Initial release
Revision 1.1Nov 22, 2023Group: Data collection / Database references ...Data collection / Database references / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.2Nov 6, 2024Group: Structure summary / Category: 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
C: Epidermal growth factor receptor
D: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)152,47111
Polymers150,6024
Non-polymers1,8687
Water17,114950
1
A: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,0912
Polymers37,6511
Non-polymers4401
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,0912
Polymers37,6511
Non-polymers4401
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,1624
Polymers37,6511
Non-polymers5113
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,1273
Polymers37,6511
Non-polymers4762
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)168.194, 74.385, 120.460
Angle α, β, γ (deg.)90.00, 118.32, 90.00
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11C-1103-

CL

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Components

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


Mass: 37650.598 Da / Num. of mol.: 4 / Mutation: T790M
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-1E8 / 1-{(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl}prop-2-en-1-one / Imbruvica / PCI-32765


Mass: 440.497 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C25H24N6O2
#3: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Cl
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 950 / 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: 1

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Sample preparation

CrystalDensity Matthews: 2.2 Å3/Da / Density % sol: 44.04 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 5
Details: 0.1 M sodium citrate (pH 5.0), 12% PEG 10000, 3% dioxane, 5 mM TCEP

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL17U1 / Wavelength: 0.9793 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Jan 26, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9793 Å / Relative weight: 1
ReflectionResolution: 1.95→50 Å / Num. obs: 94954 / % possible obs: 99.42 % / Redundancy: 3.2 % / Rpim(I) all: 0.095 / Net I/σ(I): 7.9
Reflection shellResolution: 1.95→2.02 Å

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Processing

Software
NameVersionClassification
PHENIX(dev_2400)refinement
DENZOdata reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3IKA

3ika


Resolution: 1.95→41.628 Å / SU ML: 0.21 / Cross valid method: FREE R-VALUE / σ(F): 1.98 / Phase error: 22.95 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2215 4744 5 %
Rwork0.2019 --
obs0.2029 94954 99.42 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.95→41.628 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9611 0 135 950 10696
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01210063
X-RAY DIFFRACTIONf_angle_d1.38713643
X-RAY DIFFRACTIONf_dihedral_angle_d26.0593956
X-RAY DIFFRACTIONf_chiral_restr0.1121528
X-RAY DIFFRACTIONf_plane_restr0.0091705
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.95-1.97220.27971400.26432894X-RAY DIFFRACTION97
1.9722-1.99540.31570.26423041X-RAY DIFFRACTION100
1.9954-2.01970.28561500.26122990X-RAY DIFFRACTION100
2.0197-2.04530.2991780.25052988X-RAY DIFFRACTION100
2.0453-2.07220.22851540.2452990X-RAY DIFFRACTION100
2.0722-2.10060.28091630.23893006X-RAY DIFFRACTION100
2.1006-2.13060.24931410.22353025X-RAY DIFFRACTION100
2.1306-2.16240.24811440.22842989X-RAY DIFFRACTION100
2.1624-2.19620.25031490.21483046X-RAY DIFFRACTION100
2.1962-2.23220.21511610.20482978X-RAY DIFFRACTION99
2.2322-2.27070.22951500.21273017X-RAY DIFFRACTION100
2.2707-2.3120.241780.21272982X-RAY DIFFRACTION100
2.312-2.35640.27261660.21723016X-RAY DIFFRACTION100
2.3564-2.40450.24141600.22023005X-RAY DIFFRACTION100
2.4045-2.45680.23731460.21652993X-RAY DIFFRACTION100
2.4568-2.51390.25471670.21553005X-RAY DIFFRACTION100
2.5139-2.57680.21851670.22072995X-RAY DIFFRACTION100
2.5768-2.64650.23231620.20823007X-RAY DIFFRACTION100
2.6465-2.72430.22191510.20382987X-RAY DIFFRACTION100
2.7243-2.81220.24461550.21263045X-RAY DIFFRACTION100
2.8122-2.91270.24351900.20592971X-RAY DIFFRACTION100
2.9127-3.02930.24091580.20263012X-RAY DIFFRACTION100
3.0293-3.16710.21111380.19583053X-RAY DIFFRACTION100
3.1671-3.3340.19991680.193007X-RAY DIFFRACTION100
3.334-3.54280.19411650.18833045X-RAY DIFFRACTION100
3.5428-3.81620.22541770.17623000X-RAY DIFFRACTION99
3.8162-4.19990.15671550.16063004X-RAY DIFFRACTION99
4.1999-4.80690.171630.16653039X-RAY DIFFRACTION99
4.8069-6.05320.20651530.19213043X-RAY DIFFRACTION99
6.0532-41.63790.23771380.21823037X-RAY DIFFRACTION96

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