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- PDB-7t4i: Crystal Structure of wild type EGFR in complex with TAK-788 -

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Basic information

Entry
Database: PDB / ID: 7t4i
TitleCrystal Structure of wild type EGFR in complex with TAK-788
ComponentsEpidermal growth factor receptor
KeywordsHYDROLASE / Kinase / Inhibitor / Complex / covalent
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 / morphogenesis of an epithelial fold / ERBB2 Activates PTK6 Signaling / intracellular vesicle / Signaling by EGFR / response to cobalamin / transmembrane receptor protein tyrosine kinase activator activity / protein tyrosine kinase activator activity / negative regulation of epidermal growth factor receptor signaling pathway / Signaling by ERBB4 / regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / eyelid development in camera-type eye / protein insertion into membrane / cerebral cortex cell migration / ERBB2 Regulates Cell Motility / regulation of JNK cascade / : / PI3K events in ERBB2 signaling / positive regulation of cyclin-dependent protein serine/threonine kinase activity / negative regulation of mitotic cell cycle / hair follicle development / MAP kinase kinase kinase activity / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / embryonic placenta development / positive regulation of bone resorption / positive regulation of G1/S transition of mitotic cell cycle / GAB1 signalosome / positive regulation of nitric oxide mediated signal transduction / salivary gland morphogenesis / peptidyl-tyrosine autophosphorylation / regulation of peptidyl-tyrosine phosphorylation / positive regulation of phosphorylation / positive regulation of glial cell proliferation / positive regulation of vasoconstriction / Signaling by ERBB2 / cellular response to epidermal growth factor stimulus / cellular response to cadmium ion / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / positive regulation of DNA repair / EGFR Transactivation by Gastrin / GRB2 events in ERBB2 signaling / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / transmembrane receptor protein tyrosine kinase activity / SHC1 events in ERBB2 signaling / ossification / positive regulation of synaptic transmission, glutamatergic / neurogenesis / cellular response to dexamethasone stimulus / 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 / NOTCH3 Activation and Transmission of Signal to the Nucleus / positive regulation of epithelial cell proliferation / astrocyte activation / liver regeneration / positive regulation of protein localization to plasma membrane / EGFR downregulation / cell surface receptor protein tyrosine kinase signaling pathway / cellular response to amino acid stimulus / positive regulation of smooth muscle cell proliferation / Signaling by ERBB2 TMD/JMD mutants / positive regulation of MAP kinase activity / clathrin-coated endocytic vesicle membrane / lung development / Constitutive Signaling by EGFRvIII / Signaling by ERBB2 ECD mutants / epidermal growth factor receptor signaling pathway / Signaling by ERBB2 KD Mutants / negative regulation of protein catabolic process / receptor protein-tyrosine kinase / Downregulation of ERBB2 signaling / kinase binding / 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 / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / 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-R28 / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.61 Å
AuthorsSkene, R.J. / Lane, W.
Funding support1items
OrganizationGrant numberCountry
Other private
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2022
Title: Discovery of mobocertinib, a potent, oral inhibitor of EGFR exon 20 insertion mutations in non-small cell lung cancer.
Authors: Huang, W.S. / Li, F. / Gong, Y. / Zhang, Y. / Youngsaye, W. / Xu, Y. / Zhu, X. / Greenfield, M.T. / Kohlmann, A. / Taslimi, P.M. / Toms, A. / Zech, S.G. / Zhou, T. / Das, B. / Jang, H.G. / ...Authors: Huang, W.S. / Li, F. / Gong, Y. / Zhang, Y. / Youngsaye, W. / Xu, Y. / Zhu, X. / Greenfield, M.T. / Kohlmann, A. / Taslimi, P.M. / Toms, A. / Zech, S.G. / Zhou, T. / Das, B. / Jang, H.G. / Tugnait, M. / Ye, Y.E. / Gonzalvez, F. / Baker, T.E. / Nadworny, S. / Ning, Y. / Wardwell, S.D. / Zhang, S. / Gould, A.E. / Hu, Y. / Lane, W. / Skene, R.J. / Zou, H. / Clackson, T. / Narasimhan, N.I. / Rivera, V.M. / Dalgarno, D.C. / Shakespeare, W.C.
History
DepositionDec 10, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 7, 2022Provider: repository / Type: Initial release
Revision 1.1Oct 25, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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)37,9492
Polymers37,3611
Non-polymers5881
Water97354
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)146.652, 146.652, 146.652
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number197
Space group name H-MI23
Components on special symmetry positions
IDModelComponents
11A-2651-

HOH

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Components

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


Mass: 37361.184 Da / Num. of mol.: 1
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-R28 / propan-2-yl 2-[[4-[2-(dimethylamino)ethyl-methyl-amino]-2-methoxy-5-(propanoylamino)phenyl]amino]-4-(1-methylindol-3-yl)pyrimidine-5-carboxylate / Mobocertinib, bound form / Mobocertinib


Mass: 587.712 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C32H41N7O4 / Feature type: SUBJECT OF INVESTIGATION / Comment: inhibitor*YM
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 54 / 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: 3.52 Å3/Da / Density % sol: 65.03 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 0.1M Bis-tris pH 6.5, 0.2M lithium sulfate, 24% PEG 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 0.987 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Sep 9, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.987 Å / Relative weight: 1
ReflectionResolution: 2.61→46.42 Å / Num. obs: 16117 / % possible obs: 100 % / Redundancy: 10.9 % / CC1/2: 0.999 / Rmerge(I) obs: 0.114 / Rpim(I) all: 0.036 / Rrim(I) all: 0.119 / Net I/σ(I): 17.8
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
2.61-2.7310.52.5182079119720.3830.8112.6471.1100
9.04-46.389.20.023386841910.0080.02474.299

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Processing

Software
NameVersionClassification
Aimless0.7.4data scaling
REFMAC5.8.0257refinement
PDB_EXTRACT3.27data extraction
HKL-2000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3W33

3w33


Resolution: 2.61→46.42 Å / Cor.coef. Fo:Fc: 0.966 / Cor.coef. Fo:Fc free: 0.938 / SU B: 28.339 / SU ML: 0.254 / SU R Cruickshank DPI: 0.3445 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.344 / ESU R Free: 0.259 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2382 755 4.7 %RANDOM
Rwork0.1815 ---
obs0.1843 15351 99.89 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 206.37 Å2 / Biso mean: 83.632 Å2 / Biso min: 41.39 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å20 Å20 Å2
2--0 Å20 Å2
3---0 Å2
Refinement stepCycle: final / Resolution: 2.61→46.42 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2477 0 43 54 2574
Biso mean--92.81 70.7 -
Num. residues----309
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0040.0122577
X-RAY DIFFRACTIONr_angle_refined_deg1.1711.6593488
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.4935307
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.97422.619126
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.3615469
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.4351515
X-RAY DIFFRACTIONr_chiral_restr0.0890.2327
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.021983
LS refinement shellResolution: 2.61→2.678 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.363 58 -
Rwork0.349 1121 -
all-1179 -
obs--99.75 %
Refinement TLS params.Method: refined / Origin x: -8.3834 Å / Origin y: 25.0658 Å / Origin z: 58.935 Å
111213212223313233
T0.1657 Å2-0.0828 Å20.0483 Å2-0.111 Å20.045 Å2--0.1178 Å2
L1.9997 °20.7819 °2-0.5483 °2-0.8709 °2-0.677 °2--0.5413 °2
S-0.2497 Å °0.2048 Å °0.1597 Å °-0.1569 Å °0.2306 Å °0.0533 Å °0.1288 Å °-0.1441 Å °0.0191 Å °

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