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- PDB-2jit: Crystal structure of EGFR kinase domain T790M mutation -

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Basic information

Entry
Database: PDB / ID: 2jit
TitleCrystal structure of EGFR kinase domain T790M mutation
ComponentsEPIDERMAL GROWTH FACTOR RECEPTOR
KeywordsTRANSFERASE / EGFR / T790M / KINASE / RECEPTOR / CELL CYCLE / PHOSPHORYLATION / DISEASE MUTATION / NUCLEOTIDE-BINDING / TYROSINE-PROTEIN KINASE / ANTI-ONCOGENE / EPIDERMAL GROWTH FACTOR / ATP-BINDING
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 / PTK6 promotes HIF1A stabilization / ERBB2 Activates PTK6 Signaling / 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 / Signaling by ERBB4 / Respiratory syncytial virus (RSV) attachment and entry / PI3K events in ERBB2 signaling / positive regulation of phosphorylation / 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 / ossification / 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 / cellular response to amino acid stimulus / SHC1 events in ERBB2 signaling / positive regulation of fibroblast proliferation / cellular response to epidermal growth factor stimulus / basal plasma membrane / positive regulation of DNA replication / positive regulation of DNA repair / phosphatidylinositol 3-kinase/protein kinase B signal transduction / Signal transduction by L1 / cellular response to estradiol stimulus / positive regulation of protein localization to plasma membrane / negative regulation of protein catabolic process / clathrin-coated endocytic vesicle membrane / NOTCH3 Activation and Transmission of Signal to the Nucleus / cell-cell adhesion / Signaling by ERBB2 TMD/JMD mutants / EGFR downregulation / Constitutive Signaling by EGFRvIII / receptor protein-tyrosine kinase / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / positive regulation of miRNA transcription / positive regulation of protein phosphorylation / cell junction / epidermal growth factor receptor signaling pathway / kinase binding / ruffle membrane / Downregulation of ERBB2 signaling / Constitutive Signaling by Aberrant PI3K in Cancer / HCMV Early Events / positive regulation of canonical Wnt signaling pathway / actin filament binding / PIP3 activates AKT signaling / neuron differentiation / transmembrane signaling receptor activity / positive regulation of cell growth / Cargo recognition for clathrin-mediated endocytosis / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / Clathrin-mediated endocytosis / nuclear membrane / ATPase binding / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / virus receptor activity / 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 / signaling receptor complex / cell surface receptor signaling pathway / Extra-nuclear estrogen signaling / endosome / 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: 3.1 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. / 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
Remark 700 SHEET DETERMINATION METHOD: AUTHOR PROVIDED.

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: EPIDERMAL GROWTH FACTOR RECEPTOR
B: EPIDERMAL GROWTH FACTOR RECEPTOR


Theoretical massNumber of molelcules
Total (without water)74,6682
Polymers74,6682
Non-polymers00
Water1,31573
1
A: EPIDERMAL GROWTH FACTOR RECEPTOR


Theoretical massNumber of molelcules
Total (without water)37,3341
Polymers37,3341
Non-polymers00
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPQS
2
B: EPIDERMAL GROWTH FACTOR RECEPTOR


Theoretical massNumber of molelcules
Total (without water)37,3341
Polymers37,3341
Non-polymers00
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPQS
Unit cell
Length a, b, c (Å)53.889, 90.304, 164.347
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: 37334.219 Da / Num. of mol.: 2 / Fragment: KINASE DOMAIN, RESIDUES 696-1022 / 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: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 73 / 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 MUTATION

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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: 19-ID / Wavelength: 0.97924
DetectorType: ADSC CCD / Detector: CCD / Date: Feb 15, 2007 / Details: MIRRORS
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97924 Å / Relative weight: 1
ReflectionResolution: 3.1→50 Å / Num. obs: 16223 / % possible obs: 99.2 % / Observed criterion σ(I): -3 / Redundancy: 9.1 % / Rmerge(I) obs: 0.1 / Net I/σ(I): 24
Reflection shellResolution: 3.1→3.34 Å / Redundancy: 7.8 % / Rmerge(I) obs: 0.38 / Mean I/σ(I) obs: 5.5 / % possible all: 96.1

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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 2ITN

2itn


Resolution: 3.1→24.42 Å / Cor.coef. Fo:Fc: 0.922 / Cor.coef. Fo:Fc free: 0.893 / Cross valid method: THROUGHOUT / ESU R Free: 0.458 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.249 759 5.1 %RANDOM
Rwork0.207 ---
obs0.209 14268 99.2 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 49 Å2
Baniso -1Baniso -2Baniso -3
1-0.02 Å20 Å20 Å2
2---0.01 Å20 Å2
3----0.01 Å2
Refinement stepCycle: LAST / Resolution: 3.1→24.42 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4813 0 0 73 4886
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0160.0224914
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.3111.9736651
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg8.245604
X-RAY DIFFRACTIONr_dihedral_angle_2_deg40.20223.911202
X-RAY DIFFRACTIONr_dihedral_angle_3_deg20.73915882
X-RAY DIFFRACTIONr_dihedral_angle_4_deg22.5161529
X-RAY DIFFRACTIONr_chiral_restr0.0780.2751
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.023618
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined0.2950.22613
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined0.3350.23390
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.2020.2213
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2120.251
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.4240.21
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.8621.53042
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.6524905
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it2.02131872
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it3.5824.51746
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: 3.1→3.18 Å / Total num. of bins used: 20 /
RfactorNum. reflection
Rfree0.422 50
Rwork0.315 929

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