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- PDB-7aei: Studies Towards a Reversible EGFR C797S Triple Mutant Inhibitor Series -

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Basic information

Entry
Database: PDB / ID: 7aei
TitleStudies Towards a Reversible EGFR C797S Triple Mutant Inhibitor Series
ComponentsEpidermal growth factor receptor
KeywordsCELL CYCLE / EGFR
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-R85 / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.65 Å
AuthorsHargreaves, D.
CitationJournal: Cancer Res. / Year: 2019
Title: Abstract 4451: Evaluation of the therapeutic potential of phosphine oxide pyrazole inhibitors in tumors harboring EGFR C797S mutation
Authors: Floch, N. / Finlay, M.R.V. / Bianco, A. / Bickerton, S. / Colclough, N. / Cross, D.A. / Cuomo, E.M. / Guerot, C.M. / Hargreaves, D. / Martin, M.J. / McKerrecher, D. / O'Neill, D.J. / Orme, J. ...Authors: Floch, N. / Finlay, M.R.V. / Bianco, A. / Bickerton, S. / Colclough, N. / Cross, D.A. / Cuomo, E.M. / Guerot, C.M. / Hargreaves, D. / Martin, M.J. / McKerrecher, D. / O'Neill, D.J. / Orme, J.P. / Rahi, A. / Smith, P.D. / Ward, R.A.
History
DepositionSep 17, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 2, 2021Provider: repository / Type: Initial release
Revision 1.1May 1, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)38,0572
Polymers37,4481
Non-polymers6091
Water19811
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area16300 Å2
MethodPISA
Unit cell
Length a, b, c (Å)145.650, 145.650, 145.650
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: 37448.262 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: Spodoptera frugiperda (fall armyworm)
References: UniProt: P00533, receptor protein-tyrosine kinase
#2: Chemical ChemComp-R85 / 5-chloranyl-~{N}2-[4-[4-(dimethylamino)piperidin-1-yl]-2-methoxy-5-(1-methylpyrazol-4-yl)phenyl]-~{N}4-(2-dimethylphosphorylphenyl)pyrimidine-2,4-diamine


Mass: 609.102 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C30H38ClN8O2P / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 11 / 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: 3.27 Å3/Da / Density % sol: 62.43 % / Description: rhombohedral crystals
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 7.5 / Details: Trisodium citrate 0.68M

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SOLEIL / Beamline: PROXIMA 1 / Wavelength: 0.9898 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Jun 3, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9898 Å / Relative weight: 1
ReflectionResolution: 2.65→46.06 Å / Num. obs: 15041 / % possible obs: 99.8 % / Redundancy: 8.6 % / Biso Wilson estimate: 109.85 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.063 / Rpim(I) all: 0.023 / Rrim(I) all: 0.068 / Net I/σ(I): 17.5 / Num. measured all: 128862
Reflection shellResolution: 2.65→2.72 Å / Redundancy: 8.4 % / Rmerge(I) obs: 0.935 / Mean I/σ(I) obs: 1.7 / Num. measured all: 9128 / Num. unique obs: 1088 / CC1/2: 0.791 / Rpim(I) all: 0.341 / Rrim(I) all: 0.996 / Net I/σ(I) obs: 1.7 / % possible all: 98.2

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
Aimless0.5.17data scaling
PDB_EXTRACT3.25data extraction
xia2data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: in house

Resolution: 2.65→46.06 Å / Cor.coef. Fo:Fc: 0.96 / Cor.coef. Fo:Fc free: 0.947 / SU R Cruickshank DPI: 0.381 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.36 / SU Rfree Blow DPI: 0.249 / SU Rfree Cruickshank DPI: 0.256
RfactorNum. reflection% reflectionSelection details
Rfree0.234 752 5 %RANDOM
Rwork0.194 ---
obs0.196 15041 99.9 %-
Displacement parametersBiso max: 200.06 Å2 / Biso mean: 94.79 Å2 / Biso min: 52.45 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å20 Å20 Å2
2--0 Å20 Å2
3---0 Å2
Refine analyzeLuzzati coordinate error obs: 0.38 Å
Refinement stepCycle: final / Resolution: 2.65→46.06 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2528 0 42 11 2581
Biso mean--97.17 84.7 -
Num. residues----315
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d935SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes429HARMONIC5
X-RAY DIFFRACTIONt_it2637HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion334SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact2880SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d2637HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg3569HARMONIC21.19
X-RAY DIFFRACTIONt_omega_torsion2.87
X-RAY DIFFRACTIONt_other_torsion20.83
LS refinement shellResolution: 2.65→2.68 Å / Rfactor Rfree error: 0 / Total num. of bins used: 37
RfactorNum. reflection% reflection
Rfree0.3507 20 4.91 %
Rwork0.3323 387 -
all0.3333 407 -
obs--97.57 %

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