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- PDB-7oxb: Crystal structure of EGFR double mutant (T790M/L858R) in complex ... -

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Basic information

Entry
Database: PDB / ID: 7oxb
TitleCrystal structure of EGFR double mutant (T790M/L858R) in complex with compound 6.
ComponentsEpidermal growth factor receptor
KeywordsTRANSFERASE / Kinase / inhibitor / EGFR / mutant
Function / homology
Function and homology information


response to hydroxyisoflavone / multivesicular body, internal vesicle lumen / positive regulation of protein kinase C activity / positive regulation of prolactin secretion / negative regulation of cardiocyte differentiation / 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 protein kinase C activity / positive regulation of prolactin secretion / negative regulation of cardiocyte differentiation / 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 / epidermal growth factor binding / response to UV-A / tongue development / PLCG1 events in ERBB2 signaling / midgut development / hydrogen peroxide metabolic process / regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / ERBB2-EGFR signaling pathway / PTK6 promotes HIF1A stabilization / digestive tract morphogenesis / morphogenesis of an epithelial fold / ERBB2 Activates PTK6 Signaling / intracellular vesicle / Signaling by EGFR / transmembrane receptor protein tyrosine kinase activator activity / negative regulation of epidermal growth factor receptor signaling pathway / protein tyrosine kinase activator activity / response to cobalamin / Signaling by ERBB4 / eyelid development in camera-type eye / protein insertion into membrane / cerebral cortex cell migration / ERBB2 Regulates Cell Motility / regulation of JNK cascade / Respiratory syncytial virus (RSV) attachment and entry / PI3K events in ERBB2 signaling / positive regulation of cyclin-dependent protein serine/threonine kinase activity / negative regulation of mitotic cell cycle / MAP kinase kinase kinase activity / hair follicle development / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / embryonic placenta development / positive regulation of bone resorption / GAB1 signalosome / positive regulation of G1/S transition of mitotic cell cycle / salivary gland morphogenesis / peptidyl-tyrosine autophosphorylation / positive regulation of phosphorylation / regulation of peptidyl-tyrosine phosphorylation / positive regulation of vasoconstriction / positive regulation of glial cell proliferation / Signaling by ERBB2 / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / cellular response to epidermal growth factor stimulus / cellular response to cadmium ion / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / GRB2 events in ERBB2 signaling / transmembrane receptor protein tyrosine kinase activity / positive regulation of DNA repair / regulation of ERK1 and ERK2 cascade / SHC1 events in ERBB2 signaling / ossification / cellular response to dexamethasone stimulus / neurogenesis / positive regulation of synaptic transmission, glutamatergic / positive regulation of epithelial cell proliferation / neuron projection morphogenesis / basal plasma membrane / epithelial cell proliferation / positive regulation of superoxide anion generation / positive regulation of DNA replication / Signal transduction by L1 / cellular response to estradiol stimulus / NOTCH3 Activation and Transmission of Signal to the Nucleus / astrocyte activation / liver regeneration / cellular response to amino acid stimulus / positive regulation of protein localization to plasma membrane / lung development / EGFR downregulation / Signaling by ERBB2 TMD/JMD mutants / positive regulation of smooth muscle cell proliferation / positive regulation of MAP kinase activity / Constitutive Signaling by EGFRvIII / clathrin-coated endocytic vesicle membrane / Signaling by ERBB2 ECD mutants / epidermal growth factor receptor signaling pathway / Signaling by ERBB2 KD Mutants / receptor protein-tyrosine kinase / negative regulation of protein catabolic process / kinase binding / Downregulation of ERBB2 signaling / positive regulation of miRNA transcription / cell-cell adhesion / peptidyl-tyrosine phosphorylation / ruffle membrane
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 / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Chem-35Z / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.56 Å
AuthorsCollie, G.W.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2021
Title: Discovery and optimization of covalent EGFR T790M/L858R mutant inhibitors".
Authors: Hoogenboom, N. / Demont, D. / de Zwart, E. / Verkaik, S. / Emmelot, M. / van de Kar, B. / Kaptein, A. / Barf, T.
History
DepositionJun 22, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 20, 2021Provider: repository / Type: Initial release

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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)37,7682
Polymers37,3241
Non-polymers4431
Water55831
1
A: Epidermal growth factor receptor
hetero molecules

A: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)75,5364
Polymers74,6492
Non-polymers8872
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_655-x+1,-y,z1
Buried area3160 Å2
ΔGint0 kcal/mol
Surface area29670 Å2
MethodPISA
Unit cell
Length a, b, c (Å)147.715, 147.715, 147.715
Angle α, β, γ (deg.)90.000, 90.000, 90.000
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: 37324.273 Da / Num. of mol.: 1 / Fragment: KINASE DOMAIN
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EGFR, ERBB, ERBB1, HER1 / Production host: Escherichia coli (E. coli)
References: UniProt: P00533, receptor protein-tyrosine kinase
#2: Chemical ChemComp-35Z / 2-[2-(3-methoxyphenyl)pyrimidin-4-yl]-1'-prop-2-enoyl-spiro[5,6-dihydro-1~{H}-pyrrolo[3,2-c]pyridine-7,4'-piperidine]-4-one


Mass: 443.498 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H25N5O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 31 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 3.67 Å3/Da / Density % sol: 66.53 %
Crystal growTemperature: 293 K / Method: vapor diffusion / Details: Unknown

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Feb 24, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.56→104.45 Å / Num. obs: 16941 / % possible obs: 97.3 % / Redundancy: 3 % / Rsym value: 0.07 / Net I/σ(I): 11.34
Reflection shellResolution: 2.56→2.81 Å / Redundancy: 3 % / Num. unique obs: 4103 / Rsym value: 0.441 / % possible all: 98.5

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Processing

Software
NameVersionClassification
REFMAC5.6.0117refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: NONE

Resolution: 2.56→104.45 Å / Cor.coef. Fo:Fc: 0.945 / Cor.coef. Fo:Fc free: 0.929 / SU B: 16.311 / SU ML: 0.171 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.324 / ESU R Free: 0.233 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2274 910 5.4 %RANDOM
Rwork0.1988 ---
obs0.2003 16030 97.29 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso max: 133.37 Å2 / Biso mean: 31.95 Å2 / Biso min: 20.99 Å2
Refinement stepCycle: final / Resolution: 2.56→104.45 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2442 0 33 31 2506
Biso mean--43.75 50.06 -
Num. residues----305
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.022447
X-RAY DIFFRACTIONr_bond_other_d0.0020.021708
X-RAY DIFFRACTIONr_angle_refined_deg1.0411.9893324
X-RAY DIFFRACTIONr_angle_other_deg0.96434121
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.1625301
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.50424.08693
X-RAY DIFFRACTIONr_dihedral_angle_3_deg10.93115417
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.3051512
X-RAY DIFFRACTIONr_chiral_restr0.0590.2376
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0212656
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02470
LS refinement shellResolution: 2.561→2.627 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.362 66 -
Rwork0.345 1103 -
all-1169 -
obs--97.25 %

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