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- PDB-6duk: EGFR with an allosteric inhibitor -

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Basic information

Entry
Database: PDB / ID: 6duk
TitleEGFR with an allosteric inhibitor
ComponentsEpidermal growth factor receptor
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Allosteric inhibitor / EGFR / ONCOPROTEIN / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


positive regulation of protein kinase C activity / multivesicular body, internal vesicle lumen / positive regulation of prolactin secretion / negative regulation of cardiocyte differentiation / response to hydroxyisoflavone / diterpenoid metabolic process / 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 / positive regulation of prolactin secretion / negative regulation of cardiocyte differentiation / response to hydroxyisoflavone / diterpenoid metabolic process / Shc-EGFR complex / Inhibition of Signaling by Overexpressed EGFR / ovulation cycle / EGFR interacts with phospholipase C-gamma / positive regulation of mucus secretion / epidermal growth factor binding / regulation of peptidyl-tyrosine phosphorylation / response to UV-A / tongue development / PLCG1 events in ERBB2 signaling / midgut development / ERBB2-EGFR signaling pathway / digestive tract morphogenesis / hydrogen peroxide metabolic process / morphogenesis of an epithelial fold / PTK6 promotes HIF1A stabilization / ERBB2 Activates PTK6 Signaling / Signaling by EGFR / intracellular vesicle / response to cobalamin / 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 / Signaling by ERBB4 / Respiratory syncytial virus (RSV) attachment and entry / PI3K events in ERBB2 signaling / negative regulation of mitotic cell cycle / MAP kinase kinase kinase activity / hair follicle development / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / positive regulation of G1/S transition of mitotic cell cycle / GAB1 signalosome / positive regulation of bone resorption / embryonic placenta development / positive regulation of phosphorylation / salivary gland morphogenesis / peptidyl-tyrosine autophosphorylation / positive regulation of peptidyl-serine phosphorylation / positive regulation of glial cell proliferation / positive regulation of vasoconstriction / Signaling by ERBB2 / transmembrane receptor protein tyrosine kinase activity / GRB2 events in EGFR signaling / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / GRB2 events in ERBB2 signaling / SHC1 events in ERBB2 signaling / cellular response to epidermal growth factor stimulus / cellular response to dexamethasone stimulus / positive regulation of synaptic transmission, glutamatergic / ossification / positive regulation of DNA repair / neuron projection morphogenesis / positive regulation of superoxide anion generation / positive regulation of epithelial cell proliferation / liver regeneration / epithelial cell proliferation / basal plasma membrane / Signal transduction by L1 / positive regulation of DNA replication / positive regulation of protein localization to plasma membrane / astrocyte activation / phosphatidylinositol 3-kinase/protein kinase B signal transduction / NOTCH3 Activation and Transmission of Signal to the Nucleus / cellular response to amino acid stimulus / positive regulation of smooth muscle cell proliferation / cellular response to estradiol stimulus / lung development / EGFR downregulation / synaptic membrane / Signaling by ERBB2 TMD/JMD mutants / clathrin-coated endocytic vesicle membrane / placental growth factor receptor activity / insulin receptor activity / vascular endothelial growth factor receptor activity / Constitutive Signaling by EGFRvIII / hepatocyte growth factor receptor activity / macrophage colony-stimulating factor receptor activity / platelet-derived growth factor alpha-receptor activity / platelet-derived growth factor beta-receptor activity / stem cell factor receptor activity / boss receptor activity / protein tyrosine kinase collagen receptor activity / brain-derived neurotrophic factor receptor activity / transmembrane-ephrin receptor activity / GPI-linked ephrin receptor activity / epidermal growth factor receptor activity / fibroblast growth factor receptor activity / insulin-like growth factor receptor activity / Signaling by ERBB2 ECD mutants
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
PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER / Chem-JBJ / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.2 Å
AuthorsPark, E. / Eck, M.J.
Funding support United States, 3items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)R01CA201049 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)P01CA154303 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)R50CA221830 United States
CitationJournal: Cancer Discov / Year: 2019
Title: Single and Dual Targeting of Mutant EGFR with an Allosteric Inhibitor.
Authors: To, C. / Jang, J. / Chen, T. / Park, E. / Mushajiang, M. / De Clercq, D.J.H. / Xu, M. / Wang, S. / Cameron, M.D. / Heppner, D.E. / Shin, B.H. / Gero, T.W. / Yang, A. / Dahlberg, S.E. / Wong, ...Authors: To, C. / Jang, J. / Chen, T. / Park, E. / Mushajiang, M. / De Clercq, D.J.H. / Xu, M. / Wang, S. / Cameron, M.D. / Heppner, D.E. / Shin, B.H. / Gero, T.W. / Yang, A. / Dahlberg, S.E. / Wong, K.K. / Eck, M.J. / Gray, N.S. / Janne, P.A.
History
DepositionJun 21, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 5, 2019Provider: repository / Type: Initial release
Revision 1.1Jul 17, 2019Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation_author.identifier_ORCID
Revision 1.2Dec 4, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.3Oct 11, 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 / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _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
E: Epidermal growth factor receptor
F: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)232,79224
Polymers226,3486
Non-polymers6,44518
Water11,602644
1
A: Epidermal growth factor receptor
B: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)77,5978
Polymers75,4492
Non-polymers2,1486
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5090 Å2
ΔGint-41 kcal/mol
Surface area25450 Å2
MethodPISA
2
C: Epidermal growth factor receptor
D: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)77,5978
Polymers75,4492
Non-polymers2,1486
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5020 Å2
ΔGint-40 kcal/mol
Surface area25870 Å2
MethodPISA
3
E: Epidermal growth factor receptor
F: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)77,5978
Polymers75,4492
Non-polymers2,1486
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5090 Å2
ΔGint-40 kcal/mol
Surface area25790 Å2
MethodPISA
Unit cell
Length a, b, c (Å)57.481, 94.711, 97.398
Angle α, β, γ (deg.)70.38, 77.46, 79.14
Int Tables number1
Space group name H-MP1

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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.: 6 / Mutation: T790M, 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-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 6 / Source method: isolated from a natural source / Formula: Mg
#3: Chemical
ChemComp-ANP / PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER


Mass: 506.196 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C10H17N6O12P3 / Comment: AMP-PNP, energy-carrying molecule analogue*YM
#4: Chemical
ChemComp-JBJ / (2R)-2-(5-fluoro-2-hydroxyphenyl)-2-{1-oxo-6-[4-(piperazin-1-yl)phenyl]-1,3-dihydro-2H-isoindol-2-yl}-N-(1,3-thiazol-2-yl)acetamide


Mass: 543.612 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C29H26FN5O3S
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 644 / 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: 2.08 Å3/Da / Density % sol: 40.88 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / Details: 0.1 M Bis-Tris, 22% PEG3350, 150 mM NaCl / PH range: 5.5

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Data collection

DiffractionMean temperature: 298 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-C / Wavelength: 0.987 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Nov 21, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.987 Å / Relative weight: 1
ReflectionResolution: 2.09→90.46 Å / Num. obs: 108372 / % possible obs: 97.2 % / Redundancy: 12.4 % / CC1/2: 0.996 / Rmerge(I) obs: 0.106 / Rpim(I) all: 0.063 / Net I/σ(I): 25.75
Reflection shellResolution: 2.09→2.12 Å / Rmerge(I) obs: 1.281 / Num. unique obs: 13035 / CC1/2: 0.474 / Rpim(I) all: 0.912

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Processing

Software
NameVersionClassification
PHENIX(1.11.1_2575: ???)refinement
ABSdata reduction
ABSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5D41

5d41


Resolution: 2.2→88.504 Å / SU ML: 0.29 / Cross valid method: FREE R-VALUE / σ(F): 1.96 / Phase error: 27.57 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2232 1725 1.85 %
Rwork0.19 --
obs0.1906 93295 98.07 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.2→88.504 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms14314 0 426 647 15387
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00915174
X-RAY DIFFRACTIONf_angle_d1.16420615
X-RAY DIFFRACTIONf_dihedral_angle_d9.82112476
X-RAY DIFFRACTIONf_chiral_restr0.0832289
X-RAY DIFFRACTIONf_plane_restr0.0072554
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.2-2.26470.32161420.27977564X-RAY DIFFRACTION97
2.2647-2.33780.30831430.26147553X-RAY DIFFRACTION97
2.3378-2.42140.29421420.24967615X-RAY DIFFRACTION98
2.4214-2.51840.31471410.23977627X-RAY DIFFRACTION98
2.5184-2.6330.28091450.22617616X-RAY DIFFRACTION98
2.633-2.77180.29751410.21687622X-RAY DIFFRACTION98
2.7718-2.94550.27281420.20977614X-RAY DIFFRACTION98
2.9455-3.17290.23421440.20367710X-RAY DIFFRACTION99
3.1729-3.49220.22031450.19127643X-RAY DIFFRACTION98
3.4922-3.99760.23111480.1637645X-RAY DIFFRACTION99
3.9976-5.03650.13941460.14567688X-RAY DIFFRACTION99
5.0365-88.5760.17571460.16227673X-RAY DIFFRACTION99

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