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- PDB-3ug1: Crystal structure of the mutated EGFR kinase domain (G719S/T790M)... -

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Basic information

Entry
Database: PDB / ID: 3ug1
TitleCrystal structure of the mutated EGFR kinase domain (G719S/T790M) in the apo form
ComponentsEpidermal growth factor receptor
KeywordsTRANSFERASE / kinase / tyrosine-protein kinase / ATP binding / phosphorylation / transmembrane / receptor / disease mutation / cell cycle / drug resistance
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 / epidermal growth factor binding / response to UV-A / regulation of peptidyl-tyrosine phosphorylation ...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 / epidermal growth factor binding / response to UV-A / regulation of peptidyl-tyrosine phosphorylation / PLCG1 events in ERBB2 signaling / ERBB2-EGFR signaling pathway / ERBB2 Activates PTK6 Signaling / PTK6 promotes HIF1A stabilization / Signaling by EGFR / intracellular vesicle / negative regulation of epidermal growth factor receptor signaling pathway / ERBB2 Regulates Cell Motility / Developmental Lineage of Mammary Gland Myoepithelial Cells / protein insertion into membrane / Respiratory syncytial virus (RSV) attachment and entry / Signaling by ERBB4 / PI3K events in ERBB2 signaling / positive regulation of phosphorylation / ossification / positive regulation of peptidyl-serine phosphorylation / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / MAP kinase kinase kinase activity / GAB1 signalosome / protein tyrosine kinase activator activity / positive regulation of G1/S transition of mitotic cell cycle / Signaling by ERBB2 / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / transmembrane receptor protein tyrosine kinase activity / positive regulation of epithelial cell proliferation / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / GRB2 events in ERBB2 signaling / positive regulation of fibroblast proliferation / cellular response to epidermal growth factor stimulus / SHC1 events in ERBB2 signaling / basal plasma membrane / positive regulation of DNA replication / positive regulation of DNA repair / cellular response to amino acid stimulus / phosphatidylinositol 3-kinase/protein kinase B signal transduction / Signal transduction by L1 / cellular response to estradiol stimulus / negative regulation of protein catabolic process / positive regulation of protein localization to plasma membrane / clathrin-coated endocytic vesicle membrane / cell-cell adhesion / NOTCH3 Activation and Transmission of Signal to the Nucleus / Signaling by ERBB2 TMD/JMD mutants / EGFR downregulation / receptor protein-tyrosine kinase / Constitutive Signaling by EGFRvIII / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / positive regulation of miRNA transcription / cell junction / positive regulation of protein phosphorylation / virus receptor activity / epidermal growth factor receptor signaling pathway / ruffle membrane / kinase binding / Downregulation of ERBB2 signaling / Constitutive Signaling by Aberrant PI3K in Cancer / HCMV Early Events / positive regulation of canonical Wnt signaling pathway / actin filament binding / transmembrane signaling receptor activity / neuron differentiation / PIP3 activates AKT signaling / positive regulation of cell growth / Cargo recognition for clathrin-mediated endocytosis / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / nuclear membrane / Clathrin-mediated endocytosis / ATPase binding / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / RAF/MAP kinase cascade / protein tyrosine kinase activity / double-stranded DNA binding / early endosome membrane / protein phosphatase binding / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / basolateral plasma membrane / positive regulation of MAPK cascade / learning or memory / positive regulation of ERK1 and ERK2 cascade / cell surface receptor signaling pathway / signaling receptor complex / endosome / Extra-nuclear estrogen signaling / endosome membrane / positive regulation of cell migration / cadherin binding / membrane raft
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 / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / 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: 2.75 Å
AuthorsParker, L.J. / Handa, N. / Yoshikawa, S. / Kukimoto-Niino, M. / Shirouzu, M. / Yokoyama, S.
CitationJournal: Oncogene / Year: 2013
Title: Structural basis for the altered drug sensitivities of non-small cell lung cancer-associated mutants of human epidermal growth factor receptor
Authors: Yoshikawa, S. / Kukimoto-Niino, M. / Parker, L. / Handa, N. / Terada, T. / Fujimoto, T. / Terazawa, Y. / Wakiyama, M. / Sato, M. / Sano, S. / Kobayashi, T. / Tanaka, T. / Chen, L. / Liu, Z.J. ...Authors: Yoshikawa, S. / Kukimoto-Niino, M. / Parker, L. / Handa, N. / Terada, T. / Fujimoto, T. / Terazawa, Y. / Wakiyama, M. / Sato, M. / Sano, S. / Kobayashi, T. / Tanaka, T. / Chen, L. / Liu, Z.J. / Wang, B.C. / Shirouzu, M. / Kawa, S. / Semba, K. / Yamamoto, T. / Yokoyama, S.
History
DepositionNov 2, 2011Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Mar 7, 2012Provider: repository / Type: Initial release
Revision 1.1Mar 12, 2014Group: Database references
Revision 1.2Nov 1, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Experimental preparation / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / exptl_crystal_grow / 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 / _exptl_crystal_grow.method / _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)38,2332
Polymers38,0381
Non-polymers1951
Water1629
1
A: Epidermal growth factor receptor
hetero molecules

A: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)76,4674
Polymers76,0762
Non-polymers3902
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation18_445z-1/2,-x-1/2,-y+1/21
Unit cell
Length a, b, c (Å)141.334, 141.334, 141.334
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 / Proto-oncogene c-ErbB-1 / Receptor tyrosine-protein kinase erbB-1


Mass: 38038.047 Da / Num. of mol.: 1 / Fragment: KINASE DOMAIN, UNP residues 695-1022 / Mutation: G719S, T790M
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EGFR, ERBB1 / Plasmid: pFastBac_HT_C / Cell line (production host): SF9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P00533, receptor protein-tyrosine kinase
#2: Chemical ChemComp-MES / 2-(N-MORPHOLINO)-ETHANESULFONIC ACID


Mass: 195.237 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H13NO4S / Comment: pH buffer*YM
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 9 / 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: 3.09 Å3/Da / Density % sol: 60.23 %
Crystal growTemperature: 293 K / Method: counter-diffusion / pH: 7.1
Details: COUNTER DIFFUSION IN MICROGRAVITY CONDITIONS; COUNTER-DIFFUSION METHOD USING JAXA CRYSTALLISATION BOX (JCB). 40mm X 0.5mm CAPILLARIES WERE FILLED WITH 8.1mg/ml PROTEIN SOLUTION AND INSTALLED ...Details: COUNTER DIFFUSION IN MICROGRAVITY CONDITIONS; COUNTER-DIFFUSION METHOD USING JAXA CRYSTALLISATION BOX (JCB). 40mm X 0.5mm CAPILLARIES WERE FILLED WITH 8.1mg/ml PROTEIN SOLUTION AND INSTALLED INTO JCB SYRINGE CASE FILLED WITH MOTHER LIQUOUR (1.7M Sodium CITRATE, 0.1M MES, 7.1). CRYSTALS WERE IN ORBIT FOR 2.5 MONTHS IN THE PROTEIN CRYSTALLISATION RESEARCH FACILITY ON THE JAPANESE EXPERIMENT MODULE OF THE INTERNATIONAL SPACE STATION., Counter Diffusion, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SPring-8 / Beamline: BL41XU / Wavelength: 1 Å
DetectorType: RAYONIX MX225HE / Detector: CCD / Date: Oct 27, 2009 / Details: RHODIUM-COATED MIRRORS (HORIZONTAL AND VERTICAL)
RadiationMonochromator: ROTATED-INCLINED DOUBLE-CRYSTAL / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.75→50 Å / Num. obs: 12348 / % possible obs: 99.9 % / Observed criterion σ(I): -3 / Redundancy: 5.1 % / Biso Wilson estimate: 67.04 Å2 / Rsym value: 0.09 / Net I/σ(I): 6.5
Reflection shellResolution: 2.75→2.9 Å / Redundancy: 5.1 % / Mean I/σ(I) obs: 1.8 / Num. unique all: 1782 / Rsym value: 0.42 / % possible all: 100

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Processing

Software
NameVersionClassification
HKL-2000data collection
PHASERphasing
REFMAC5.2.0019refinement
MOSFLMdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2GS2

2gs2


Resolution: 2.75→50 Å / Cor.coef. Fo:Fc: 0.943 / Cor.coef. Fo:Fc free: 0.903 / SU B: 12.121 / SU ML: 0.244 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.304 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.243 617 5 %RANDOM
Rwork0.196 ---
obs0.198 12334 99.8 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 52.17 Å2
Refinement stepCycle: LAST / Resolution: 2.75→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2301 0 12 9 2322
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0180.0222370
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.8211.9753220
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.725294
X-RAY DIFFRACTIONr_dihedral_angle_2_deg40.78124.16796
X-RAY DIFFRACTIONr_dihedral_angle_3_deg22.46215403
X-RAY DIFFRACTIONr_dihedral_angle_4_deg23.4541512
X-RAY DIFFRACTIONr_chiral_restr0.1120.2369
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.021750
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined0.2690.21106
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined0.3430.21628
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1780.268
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2940.242
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.3460.24
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.2441.51500
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.82422380
X-RAY DIFFRACTIONr_scbond_it2.8553979
X-RAY DIFFRACTIONr_scangle_it4.2944.5839
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.75→2.82 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.346 45 -
Rwork0.271 848 -
obs-848 100 %

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