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- PDB-2jiu: Crystal structure of EGFR kinase domain T790M mutation in complex... -

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Basic information

Entry
Database: PDB / ID: 2jiu
TitleCrystal structure of EGFR kinase domain T790M mutation in complex with AEE788
ComponentsEPIDERMAL GROWTH FACTOR RECEPTOR
KeywordsTRANSFERASE / CELL CYCLE / ATP-BINDING / NUCLEOTIDE-BINDING / ALTERNATIVE SPLICING / EGFR / T790M / KINASE / AEE788 / RECEPTOR / TYROSINE-PROTEIN KINASE / EPIDERMAL GROWTH FACTOR / PHOSPHORYLATION / DISEASE MUTATION / ANTI-ONCOGENE / TRANSMEMBRANE
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 / tongue development / response to UV-A / PLCG1 events in ERBB2 signaling / midgut development / ERBB2-EGFR signaling pathway / hydrogen peroxide metabolic process / morphogenesis of an epithelial fold / PTK6 promotes HIF1A stabilization / ERBB2 Activates PTK6 Signaling / digestive tract morphogenesis / Signaling by EGFR / response to cobalamin / intracellular vesicle / eyelid development in camera-type eye / negative regulation of epidermal growth factor receptor signaling pathway / 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 / 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 / positive regulation of bone resorption / GAB1 signalosome / 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 / cellular response to epidermal growth factor stimulus / SHC1 events in ERBB2 signaling / cellular response to dexamethasone stimulus / ossification / positive regulation of DNA repair / positive regulation of synaptic transmission, glutamatergic / neuron projection morphogenesis / positive regulation of superoxide anion generation / positive regulation of epithelial cell proliferation / epithelial cell proliferation / liver regeneration / basal plasma membrane / Signal transduction by L1 / positive regulation of DNA replication / positive regulation of protein localization to plasma membrane / astrocyte activation / NOTCH3 Activation and Transmission of Signal to the Nucleus / phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of smooth muscle cell proliferation / cellular response to amino acid stimulus / cellular response to estradiol stimulus / lung development / EGFR downregulation / placental growth factor receptor activity / clathrin-coated endocytic vesicle membrane / Signaling by ERBB2 TMD/JMD mutants / synaptic membrane / vascular endothelial growth factor receptor activity / 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 / boss receptor activity / protein tyrosine kinase collagen receptor activity / brain-derived neurotrophic factor receptor activity / stem cell factor receptor activity / GPI-linked ephrin receptor activity / transmembrane-ephrin receptor activity / epidermal growth factor receptor activity / fibroblast growth factor receptor activity / insulin receptor activity / insulin-like growth factor receptor activity / Constitutive Signaling by EGFRvIII / 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
Chem-AEE / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.05 Å
AuthorsYun, C.-H. / Mengwasser, K.E. / Toms, A.V. / Woo, M.S. / Greulich, H. / Wong, K.-K. / Meyerson, M. / Eck, M.J.
CitationJournal: Proc.Natl.Acad.Sci.USA / Year: 2008
Title: The T790M Mutation in Egfr Kinase Causes Drug Resistance by Increasing the Affinity for ATP.
Authors: Yun, C.-H. / Mengwasser, K.E. / Toms, A.V. / Woo, M.S. / Greulich, H. / Wong, K.-K. / Meyerson, M. / Eck, M.J.
History
DepositionJul 1, 2007Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 22, 2008Provider: repository / Type: Initial release
Revision 1.1May 7, 2011Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Dec 13, 2023Group: Data collection / Database references ...Data collection / Database references / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)75,2833
Polymers74,8432
Non-polymers4411
Water1,08160
1
A: EPIDERMAL GROWTH FACTOR RECEPTOR
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,8622
Polymers37,4211
Non-polymers4411
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPQS
2
B: EPIDERMAL GROWTH FACTOR RECEPTOR


Theoretical massNumber of molelcules
Total (without water)37,4211
Polymers37,4211
Non-polymers00
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPQS
Unit cell
Length a, b, c (Å)48.405, 88.643, 164.867
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein EPIDERMAL GROWTH FACTOR RECEPTOR / RECEPTOR TYROSINE-PROTEIN KINASE ERBB-1


Mass: 37421.301 Da / Num. of mol.: 2 / Fragment: KINASE DOMAIN, RESIDUES 695-1022 / Mutation: YES
Source method: isolated from a genetically manipulated source
Details: EGFR 696-1022 T790M / Source: (gene. exp.) HOMO SAPIENS (human) / Description: EGFR 696-1022 T790M / Plasmid: PACG2T / Cell line (production host): SF9 / Production host: SPODOPTERA FRUGIPERDA (fall armyworm) / References: UniProt: P00533, EC: 2.7.1.112
#2: Chemical ChemComp-AEE / 6-{4-[(4-ETHYLPIPERAZIN-1-YL)METHYL]PHENYL}-N-[(1R)-1-PHENYLETHYL]-7H-PYRROLO[2,3-D]PYRIMIDIN-4-AMINE


Mass: 440.583 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H32N6 / Comment: inhibitor*YM
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 60 / Source method: isolated from a natural source / Formula: H2O
Compound detailsENGINEERED RESIDUE IN CHAIN A, THR 790 TO MET ENGINEERED RESIDUE IN CHAIN B, THR 790 TO MET
Sequence detailsT790M MUTANT

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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: 2.4 Å3/Da / Density % sol: 48 % / Description: NONE
Crystal growpH: 7.5 / Details: 0.1M HEPES 7.5, 0.3M NACL, 21% PEG6K, 5MM TCEP

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-C / Wavelength: 0.97949
DetectorType: ADSC CCD / Detector: CCD / Date: Mar 11, 2007 / Details: MIRRORS
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97949 Å / Relative weight: 1
ReflectionResolution: 3.05→50 Å / Num. obs: 14268 / % possible obs: 99.8 % / Observed criterion σ(I): -3 / Redundancy: 5.8 % / Rmerge(I) obs: 0.1 / Net I/σ(I): 17.5
Reflection shellResolution: 3.05→3.29 Å / Redundancy: 4.6 % / Rmerge(I) obs: 0.39 / Mean I/σ(I) obs: 4 / % possible all: 99.4

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Processing

Software
NameVersionClassification
REFMAC5.3.0026refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2JIT

2jit


Resolution: 3.05→24.12 Å / Cor.coef. Fo:Fc: 0.932 / Cor.coef. Fo:Fc free: 0.885 / Cross valid method: THROUGHOUT / ESU R Free: 0.518 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.277 716 5.1 %RANDOM
Rwork0.211 ---
obs0.214 13366 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: 62.74 Å2
Baniso -1Baniso -2Baniso -3
1-0.09 Å20 Å20 Å2
2---0.08 Å20 Å2
3---0 Å2
Refinement stepCycle: LAST / Resolution: 3.05→24.12 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4787 0 33 60 4880
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.0224935
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.3671.9826688
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.3915609
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.56623.706197
X-RAY DIFFRACTIONr_dihedral_angle_3_deg19.44915873
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.5421530
X-RAY DIFFRACTIONr_chiral_restr0.0830.2753
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.023647
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined0.2580.22407
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined0.3270.23400
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1710.2156
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2120.252
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.2050.21
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.7851.53053
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.48424919
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it1.65431882
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it2.9094.51769
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 3.05→3.13 Å / Total num. of bins used: 20 /
RfactorNum. reflection
Rfree0.366 49
Rwork0.304 916

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