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- PDB-7tvd: Crystal structure of the kinase domain of EGFR exon-19 (del-747-7... -

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Basic information

Entry
Database: PDB / ID: 7tvd
TitleCrystal structure of the kinase domain of EGFR exon-19 (del-747-749) mutant
ComponentsEpidermal growth factor receptor
KeywordsTRANSFERASE / EGFR / exon-19 / kinase / ONCOPROTEIN
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 / epidermal growth factor receptor activity / EGFR interacts with phospholipase C-gamma / 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 / epidermal growth factor receptor activity / EGFR interacts with phospholipase C-gamma / 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 / 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 / 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 / SHC1 events in EGFR signaling / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / EGFR Transactivation by Gastrin / transmembrane receptor protein tyrosine kinase activity / 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 / positive regulation of epithelial cell proliferation / Signal transduction by L1 / 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 / Signaling by ERBB2 ECD mutants / receptor protein-tyrosine kinase / Signaling by ERBB2 KD Mutants / negative regulation of protein catabolic process / positive regulation of miRNA transcription / kinase binding / ruffle membrane / epidermal growth factor receptor signaling pathway / positive regulation of protein phosphorylation / cell morphogenesis / neuron differentiation / 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 / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / transmembrane signaling receptor activity / positive regulation of canonical Wnt signaling pathway / Clathrin-mediated endocytosis / PIP3 activates AKT signaling / ATPase binding / virus receptor activity / 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
Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.96 Å
AuthorsAshtekar, K.D. / Stayrook, S.E. / Lemmon, M.A.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)GR110199 United States
CitationJournal: Nat Commun / Year: 2022
Title: Biochemical and structural basis for differential inhibitor sensitivity of EGFR with distinct exon 19 mutations.
Authors: van Alderwerelt van Rosenburgh, I.K. / Lu, D.M. / Grant, M.J. / Stayrook, S.E. / Phadke, M. / Walther, Z. / Goldberg, S.B. / Politi, K. / Lemmon, M.A. / Ashtekar, K.D. / Tsutsui, Y.
History
DepositionFeb 4, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 16, 2022Provider: repository / Type: Initial release
Revision 1.1Aug 31, 2022Group: Database references / Category: citation / Item: _citation.title
Revision 1.2Nov 30, 2022Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.3Oct 25, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Epidermal growth factor receptor


Theoretical massNumber of molelcules
Total (without water)38,2371
Polymers38,2371
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)149.420, 149.420, 149.420
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number197
Space group name H-MI23
Space group name HallI223
Symmetry operation#1: x,y,z
#2: z,x,y
#3: y,z,x
#4: -y,-z,x
#5: z,-x,-y
#6: -y,z,-x
#7: -z,-x,y
#8: -z,x,-y
#9: y,-z,-x
#10: x,-y,-z
#11: -x,y,-z
#12: -x,-y,z
#13: x+1/2,y+1/2,z+1/2
#14: z+1/2,x+1/2,y+1/2
#15: y+1/2,z+1/2,x+1/2
#16: -y+1/2,-z+1/2,x+1/2
#17: z+1/2,-x+1/2,-y+1/2
#18: -y+1/2,z+1/2,-x+1/2
#19: -z+1/2,-x+1/2,y+1/2
#20: -z+1/2,x+1/2,-y+1/2
#21: y+1/2,-z+1/2,-x+1/2
#22: x+1/2,-y+1/2,-z+1/2
#23: -x+1/2,y+1/2,-z+1/2
#24: -x+1/2,-y+1/2,z+1/2

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Components

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


Mass: 38237.191 Da / Num. of mol.: 1
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

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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: 3.64 Å3/Da / Density % sol: 66.16 %
Crystal growTemperature: 289.15 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 28% PEG 400, 0.1 M Na Hepes pH 7.5, 0.2 M Calcium Chloride

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-C / Wavelength: 0.97918 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Mar 19, 2019 / Details: undulator
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
ReflectionResolution: 2.96→105.66 Å / Num. obs: 11749 / % possible obs: 100 % / Redundancy: 36.1 % / CC1/2: 0.999 / Rmerge(I) obs: 0.259 / Rpim(I) all: 0.044 / Rrim(I) all: 0.263 / Net I/σ(I): 15.4 / Num. measured all: 423785
Reflection shell

Diffraction-ID: 1 / % possible all: 100

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs
2.96-3.1436.16.5966784218800.4381.116.690.8
8.88-105.6633.50.0551592347610.010.05667.6

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Processing

Software
NameVersionClassification
PHENIX1.19.2_4158refinement
XDS20200417data reduction
PDB_EXTRACT3.27data extraction
SCALA3.3.22data scaling
PHASER2.8.3phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1M17

1m17


Resolution: 2.96→74.71 Å / SU ML: 0.4085 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 35.9126
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2774 561 4.79 %
Rwork0.2403 11154 -
obs0.2422 11715 99.72 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 104.92 Å2
Refinement stepCycle: LAST / Resolution: 2.96→74.71 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2338 0 0 0 2338
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00432389
X-RAY DIFFRACTIONf_angle_d0.76633234
X-RAY DIFFRACTIONf_chiral_restr0.0466364
X-RAY DIFFRACTIONf_plane_restr0.0052408
X-RAY DIFFRACTIONf_dihedral_angle_d5.2813314
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.96-3.260.39991350.36812748X-RAY DIFFRACTION99.11
3.26-3.730.331340.27492762X-RAY DIFFRACTION99.97
3.73-4.70.2731250.23712801X-RAY DIFFRACTION99.97
4.7-74.710.25461670.21532843X-RAY DIFFRACTION99.83
Refinement TLS params.Method: refined / Origin x: -60.3983808351 Å / Origin y: 7.60852047851 Å / Origin z: 25.513823797 Å
111213212223313233
T0.640381249124 Å20.0175922995993 Å2-0.0318407945647 Å2-0.720231788996 Å20.0636829115989 Å2--0.592221766045 Å2
L1.65881797857 °2-0.682138598121 °20.907586756529 °2-2.82000850974 °2-1.0673270492 °2--1.48540855374 °2
S-0.0767085760889 Å °0.165010000026 Å °0.153164561132 Å °0.174344820957 Å °-0.266258483558 Å °-0.254362724926 Å °-0.157584001204 Å °0.277904573147 Å °-0.00154830740713 Å °
Refinement TLS groupSelection details: all

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