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- PDB-1m17: Epidermal Growth Factor Receptor tyrosine kinase domain with 4-an... -

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Basic information

Entry
Database: PDB / ID: 1m17
TitleEpidermal Growth Factor Receptor tyrosine kinase domain with 4-anilinoquinazoline inhibitor erlotinib
Componentsepidermal growth factor receptor
KeywordsTRANSFERASE / tyrosine kinase domain
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 / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / GRB2 events in EGFR signaling / transmembrane receptor protein tyrosine kinase activity / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / GRB2 events in ERBB2 signaling / SHC1 events in ERBB2 signaling / ossification / basal plasma membrane / cellular response to epidermal growth factor stimulus / positive regulation of DNA repair / 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 / NOTCH3 Activation and Transmission of Signal to the Nucleus / phosphatidylinositol 3-kinase/protein kinase B signal transduction / cellular response to estradiol stimulus / clathrin-coated endocytic vesicle membrane / EGFR downregulation / Signaling by ERBB2 TMD/JMD mutants / cell-cell adhesion / Constitutive Signaling by EGFRvIII / receptor protein-tyrosine kinase / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / negative regulation of protein catabolic process / positive regulation of miRNA transcription / kinase binding / epidermal growth factor receptor signaling pathway / ruffle membrane / Downregulation of ERBB2 signaling / positive regulation of fibroblast proliferation / cell morphogenesis / neuron differentiation / positive regulation of protein phosphorylation / HCMV Early Events / Constitutive Signaling by Aberrant PI3K in Cancer / actin filament binding / cell junction / transmembrane signaling receptor activity / positive regulation of canonical Wnt signaling pathway / PIP3 activates AKT signaling / Cargo recognition for clathrin-mediated endocytosis / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / Clathrin-mediated endocytosis / ATPase binding / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / virus receptor activity / RAF/MAP kinase cascade / 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 / cell surface receptor signaling pathway / Extra-nuclear estrogen signaling / positive regulation of ERK1 and ERK2 cascade
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-AQ4 / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.6 Å
AuthorsStamos, J. / Sliwkowski, M.X. / Eigenbrot, C.
CitationJournal: J.Biol.Chem. / Year: 2002
Title: Structure of the epidermal growth factor receptor kinase domain alone and in complex with a 4-anilinoquinazoline inhibitor.
Authors: Stamos, J. / Sliwkowski, M.X. / Eigenbrot, C.
History
DepositionJun 17, 2002Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 4, 2002Provider: repository / Type: Initial release
Revision 1.1Apr 28, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Feb 14, 2024Group: 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_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_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,2692
Polymers37,8761
Non-polymers3931
Water36020
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)147.800, 147.800, 147.800
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number197
Space group name H-MI23

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Components

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


Mass: 37875.754 Da / Num. of mol.: 1 / Fragment: tyrosine kinase domain (residues 671-998)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: egfr / Plasmid: pVL1392 / Cell line (production host): SF9 / Production host: Spodoptera frugiperda (fall armyworm)
Strain (production host): autographica californica/t.nicoplusia
References: UniProt: P00533, EC: 2.7.1.112
#2: Chemical ChemComp-AQ4 / [6,7-BIS(2-METHOXY-ETHOXY)QUINAZOLINE-4-YL]-(3-ETHYNYLPHENYL)AMINE / ERLOTINIB


Mass: 393.436 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H23N3O4
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 20 / 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: 3.55 Å3/Da / Density % sol: 65.35 %
Crystal growTemperature: 292 K / Method: vapor diffusion, hanging drop / pH: 7
Details: tartrate, pH 7.0, VAPOR DIFFUSION, HANGING DROP, temperature 292K
Crystal grow
*PLUS
Details: used macroseeding
Components of the solutions
*PLUS
IDConc.Common nameCrystal-IDSol-IDDetails
11.0 Msodium potassium phosphate1reservoir
20.1 MMES1reservoirpH7.0
38 mg/mlprotein1drop

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.1 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 4 / Detector: CCD / Date: Nov 18, 2001
RadiationMonochromator: curved crystal monochromator / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.6→30 Å / Num. all: 16628 / Num. obs: 16628 / % possible obs: 100 % / Observed criterion σ(I): -3 / Redundancy: 11 % / Biso Wilson estimate: 88.5 Å2 / Rmerge(I) obs: 0.093 / Rsym value: 0.093 / Net I/σ(I): 27
Reflection shellResolution: 2.6→2.69 Å / Redundancy: 10.5 % / Rmerge(I) obs: 0.99 / Mean I/σ(I) obs: 2.8 / Num. unique all: 1635 / Rsym value: 0.99 / % possible all: 100
Reflection
*PLUS
Highest resolution: 2.6 Å / % possible obs: 100 % / Num. measured all: 182345
Reflection shell
*PLUS
% possible obs: 100 % / Num. unique obs: 1635 / Num. measured obs: 17173

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Processing

Software
NameVersionClassification
DENZOdata reduction
TRUNCATEdata reduction
AMoREphasing
X-PLOR98.1refinement
CCP4(TRUNCATE)data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: pdb entry 1FGK; poly alanine

1fgk


Resolution: 2.6→30 Å / Rfactor Rfree error: 0.011 / Data cutoff high absF: 1000000 / Data cutoff low absF: 0.001 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0.2 / Stereochemistry target values: Engh & Huber / Details: BULK SOLVENT MODEL USED
RfactorNum. reflection% reflectionSelection details
Rfree0.295 689 4.1 %RANDOM
Rwork0.251 ---
all0.2527 16628 --
obs0.251 16628 99.8 %-
Displacement parametersBiso mean: 70.4 Å2
Baniso -1Baniso -2Baniso -3
1-9.7 Å20 Å20 Å2
2--9.7 Å20 Å2
3---9.7 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.41 Å0.36 Å
Luzzati d res low-5 Å
Luzzati sigma a0.41 Å0.33 Å
Refinement stepCycle: LAST / Resolution: 2.6→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2511 0 29 20 2560
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONx_bond_d0.011
X-RAY DIFFRACTIONx_angle_deg1.5
X-RAY DIFFRACTIONx_dihedral_angle_d23.3
X-RAY DIFFRACTIONx_improper_angle_d1.81
X-RAY DIFFRACTIONx_mcbond_it4.852
X-RAY DIFFRACTIONx_mcangle_it7.223
X-RAY DIFFRACTIONx_scbond_it10.254
X-RAY DIFFRACTIONx_scangle_it13.676
LS refinement shellResolution: 2.6→2.69 Å / Rfactor Rfree error: 0.059 / Total num. of bins used: 10
RfactorNum. reflection% reflection
Rfree0.577 53 3.3 %
Rwork0.585 1560 -
obs--97.8 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1MSI_XPLOR_PARHCSDX.PROMSI_XPLOR_TOPHCSDX.PRO
X-RAY DIFFRACTION2TAR.PARTAR.TOP
X-RAY DIFFRACTION3PARWAT.PROTOPWAT.PRO
Refinement
*PLUS
Lowest resolution: 30 Å / Rfactor Rfree: 0.294
Solvent computation
*PLUS
Displacement parameters
*PLUS
Refine LS restraints
*PLUS
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONx_dihedral_angle_d
X-RAY DIFFRACTIONx_dihedral_angle_deg23.3
X-RAY DIFFRACTIONx_improper_angle_d
X-RAY DIFFRACTIONx_improper_angle_deg1.81
X-RAY DIFFRACTIONx_mcbond_it4.85
X-RAY DIFFRACTIONx_scbond_it10.25
X-RAY DIFFRACTIONx_mcangle_it7.22
X-RAY DIFFRACTIONx_scangle_it13.67

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