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- PDB-4i24: Structure of T790M EGFR kinase domain co-crystallized with dacomitinib -

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Basic information

Entry
Database: PDB / ID: 4i24
TitleStructure of T790M EGFR kinase domain co-crystallized with dacomitinib
ComponentsEpidermal growth factor receptor
KeywordsTRANSFERASE / Kinase domain / Phosphotrasfer / ATP binding
Function / homology
Function and homology information


response to hydroxyisoflavone / multivesicular body, internal vesicle lumen / positive regulation of prolactin secretion / negative regulation of cardiocyte differentiation / positive regulation of protein kinase C activity / diterpenoid metabolic process / Shc-EGFR complex / ovulation cycle / Inhibition of Signaling by Overexpressed EGFR / epidermal growth factor receptor activity ...response to hydroxyisoflavone / multivesicular body, internal vesicle lumen / positive regulation of prolactin secretion / negative regulation of cardiocyte differentiation / positive regulation of protein kinase C activity / diterpenoid metabolic process / Shc-EGFR complex / ovulation cycle / Inhibition of Signaling by Overexpressed EGFR / epidermal growth factor receptor activity / EGFR interacts with phospholipase C-gamma / positive regulation of mucus secretion / response to UV-A / epidermal growth factor binding / PLCG1 events in ERBB2 signaling / tongue development / midgut development / ERBB2-EGFR signaling pathway / hydrogen peroxide metabolic process / PTK6 promotes HIF1A stabilization / digestive tract morphogenesis / regulation of nitric-oxide synthase activity / ERBB2 Activates PTK6 Signaling / morphogenesis of an epithelial fold / intracellular vesicle / Signaling by EGFR / response to cobalamin / negative regulation of epidermal growth factor receptor signaling pathway / transmembrane receptor protein tyrosine kinase activator activity / protein tyrosine kinase activator activity / Signaling by ERBB4 / regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / protein insertion into membrane / eyelid development in camera-type eye / cerebral cortex cell migration / ERBB2 Regulates Cell Motility / regulation of JNK cascade / activation of phospholipase C activity / positive regulation of cyclin-dependent protein serine/threonine kinase activity / PI3K events in ERBB2 signaling / negative regulation of mitotic cell cycle / hair follicle development / MAP kinase kinase kinase activity / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / positive regulation of G1/S transition of mitotic cell cycle / embryonic placenta development / positive regulation of bone resorption / GAB1 signalosome / positive regulation of nitric oxide mediated signal transduction / salivary gland morphogenesis / regulation of peptidyl-tyrosine phosphorylation / peptidyl-tyrosine autophosphorylation / positive regulation of glial cell proliferation / positive regulation of phosphorylation / positive regulation of vasoconstriction / Signaling by ERBB2 / cellular response to epidermal growth factor stimulus / cellular response to cadmium ion / positive regulation of DNA repair / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / GRB2 events in ERBB2 signaling / transmembrane receptor protein tyrosine kinase activity / neurogenesis / cellular response to dexamethasone stimulus / SHC1 events in ERBB2 signaling / ossification / positive regulation of synaptic transmission, glutamatergic / basal plasma membrane / regulation of ERK1 and ERK2 cascade / neuron projection morphogenesis / positive regulation of superoxide anion generation / positive regulation of DNA replication / Signal transduction by L1 / epithelial cell proliferation / cellular response to estradiol stimulus / liver regeneration / positive regulation of epithelial cell proliferation / NOTCH3 Activation and Transmission of Signal to the Nucleus / astrocyte activation / cellular response to amino acid stimulus / positive regulation of protein localization to plasma membrane / EGFR downregulation / clathrin-coated endocytic vesicle membrane / positive regulation of smooth muscle cell proliferation / lung development / Signaling by ERBB2 TMD/JMD mutants / Constitutive Signaling by EGFRvIII / positive regulation of MAP kinase activity / Signaling by ERBB2 ECD mutants / epidermal growth factor receptor signaling pathway / Signaling by ERBB2 KD Mutants / negative regulation of protein catabolic process / cell-cell adhesion / receptor protein-tyrosine kinase / ruffle membrane / Downregulation of ERBB2 signaling / cellular response to reactive oxygen species
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 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; 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-1C9 / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.8 Å
AuthorsGajiwala, K.S. / Feng, J. / Ferre, R. / Ryan, K. / Brodsky, O. / Stewart, A.
CitationJournal: Structure / Year: 2013
Title: Insights into the Aberrant Activity of Mutant EGFR Kinase Domain and Drug Recognition.
Authors: Gajiwala, K.S. / Feng, J. / Ferre, R. / Ryan, K. / Brodsky, O. / Weinrich, S. / Kath, J.C. / Stewart, A.
History
DepositionNov 21, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 16, 2013Provider: repository / Type: Initial release
Revision 1.1Feb 27, 2013Group: Database references

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)75,8974
Polymers74,9572
Non-polymers9402
Water5,080282
1
A: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,9482
Polymers37,4781
Non-polymers4701
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,9482
Polymers37,4781
Non-polymers4701
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2960 Å2
ΔGint-19 kcal/mol
Surface area25980 Å2
MethodPISA
Unit cell
Length a, b, c (Å)35.848, 76.385, 77.961
Angle α, β, γ (deg.)67.17, 80.53, 85.67
Int Tables number1
Space group name H-MP1

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Components

#1: Protein Epidermal growth factor receptor / / Proto-oncogene c-ErbB-1 / Receptor tyrosine-protein kinase erbB-1


Mass: 37478.355 Da / Num. of mol.: 2 / Fragment: UNP residues 695-1022, EGFR kinase domain / Mutation: T790M
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EGFR, ERBB, ERBB1, HER1 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P00533, receptor protein-tyrosine kinase
#2: Chemical ChemComp-1C9 / (2E)-N-{4-[(3-chloro-4-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}-4-(piperidin-1-yl)but-2-enamide / Dacomitinib / Dacomitinib


Mass: 469.939 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H25ClFN5O2 / Comment: medication, inhibitor*YM
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 282 / 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: 2.59 Å3/Da / Density % sol: 52.49 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop
Details: 0.12-0.14 M ammonium acetate, 12-14% PEG 3350, VAPOR DIFFUSION, HANGING DROP, temperature 291K

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Data collection

DiffractionMean temperature: 98 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.1 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Sep 12, 2010 / Details: Mirrors
RadiationMonochromator: Mirrors / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.8→50 Å / Num. all: 69443 / Num. obs: 67776 / % possible obs: 97.6 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 3.9 % / Biso Wilson estimate: 18.1 Å2 / Rmerge(I) obs: 0.051 / Net I/σ(I): 23.53
Reflection shellResolution: 1.8→1.86 Å / Redundancy: 3.9 % / Rmerge(I) obs: 0.51 / Mean I/σ(I) obs: 2.8 / Num. unique all: 6726 / % possible all: 96.3

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Processing

Software
NameVersionClassification
ADSCQuantumdata collection
CNXrefinement
HKL-2000data reduction
SCALEPACKdata scaling
CNXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.8→42.55 Å / Rfactor Rfree error: 0.004 / Data cutoff high absF: 102513.62 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.239 3268 5.1 %RANDOM
Rwork0.209 ---
obs0.21 64068 91.9 %-
all-67710 --
Solvent computationSolvent model: FLAT MODEL / Bsol: 44.9926 Å2 / ksol: 0.365236 e/Å3
Displacement parametersBiso mean: 31 Å2
Baniso -1Baniso -2Baniso -3
1-7.21 Å2-1.55 Å2-0.45 Å2
2---5.56 Å20.45 Å2
3----1.64 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.27 Å0.23 Å
Luzzati d res low-5 Å
Luzzati sigma a0.29 Å0.24 Å
Refinement stepCycle: LAST / Resolution: 1.8→42.55 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4813 0 56 282 5151
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.005
X-RAY DIFFRACTIONc_angle_deg0.8
X-RAY DIFFRACTIONc_dihedral_angle_d19.4
X-RAY DIFFRACTIONc_improper_angle_d0.62
X-RAY DIFFRACTIONc_mcbond_it1.371.5
X-RAY DIFFRACTIONc_mcangle_it2.132
X-RAY DIFFRACTIONc_scbond_it2.112
X-RAY DIFFRACTIONc_scangle_it3.132.5
Refine LS restraints NCSNCS model details: NONE
LS refinement shellResolution: 1.8→1.91 Å / Rfactor Rfree error: 0.016 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.34 430 4.7 %
Rwork0.287 8812 -
obs--79.5 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1protein_rep-truncated.paramprotein-truncated.top
X-RAY DIFFRACTION2dna-rna_rep.paradna-rna.top
X-RAY DIFFRACTION3water_rep.paramwater.top
X-RAY DIFFRACTION4ion.paramion.top

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