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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


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
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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