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- PDB-9ews: Optimisation of Potent, Efficacious, Selective and Blood-Brain Ba... -

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Basic information

Entry
Database: PDB / ID: 9ews
TitleOptimisation of Potent, Efficacious, Selective and Blood-Brain Barrier Penetrating Inhibitors Targeting EGFR Exon20 Insertion Mutations
ComponentsEpidermal growth factor receptor
KeywordsSIGNALING PROTEIN / EGFR / exon20 insertion / NPG
Function / homology
Function and homology information


positive regulation of protein kinase C activity / multivesicular body, internal vesicle lumen / positive regulation of prolactin secretion / negative regulation of cardiocyte differentiation / response to hydroxyisoflavone / diterpenoid metabolic process / Shc-EGFR complex / Inhibition of Signaling by Overexpressed EGFR / ovulation cycle / EGFR interacts with phospholipase C-gamma ...positive regulation of protein kinase C activity / multivesicular body, internal vesicle lumen / positive regulation of prolactin secretion / negative regulation of cardiocyte differentiation / response to hydroxyisoflavone / diterpenoid metabolic process / Shc-EGFR complex / Inhibition of Signaling by Overexpressed EGFR / ovulation cycle / 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 / ERBB2-EGFR signaling pathway / digestive tract morphogenesis / hydrogen peroxide metabolic process / PTK6 promotes HIF1A stabilization / morphogenesis of an epithelial fold / ERBB2 Activates PTK6 Signaling / Signaling by EGFR / intracellular vesicle / response to cobalamin / negative regulation of epidermal growth factor receptor signaling pathway / eyelid development in camera-type eye / cerebral cortex cell migration / protein insertion into membrane / ERBB2 Regulates Cell Motility / positive regulation of cyclin-dependent protein serine/threonine kinase activity / Signaling by ERBB4 / protein tyrosine kinase activator activity / Respiratory syncytial virus (RSV) attachment and entry / regulation of peptidyl-tyrosine phosphorylation / PI3K events in ERBB2 signaling / negative regulation of mitotic cell cycle / MAP kinase kinase kinase activity / hair follicle development / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / positive regulation of G1/S transition of mitotic cell cycle / GAB1 signalosome / embryonic placenta development / positive regulation of bone resorption / positive regulation of phosphorylation / salivary gland morphogenesis / peptidyl-tyrosine autophosphorylation / positive regulation of glial cell proliferation / positive regulation of vasoconstriction / Signaling by ERBB2 / transmembrane receptor protein tyrosine kinase activity / GRB2 events in EGFR signaling / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / histone H3Y41 kinase activity / histone H2AXY142 kinase activity / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / GRB2 events in ERBB2 signaling / cellular response to epidermal growth factor stimulus / SHC1 events in ERBB2 signaling / cellular response to dexamethasone stimulus / positive regulation of synaptic transmission, glutamatergic / ossification / positive regulation of DNA repair / positive regulation of peptidyl-serine phosphorylation / neuron projection morphogenesis / positive regulation of superoxide anion generation / positive regulation of epithelial cell proliferation / basal plasma membrane / liver regeneration / epithelial cell proliferation / Signal transduction by L1 / neurogenesis / positive regulation of DNA replication / positive regulation of protein localization to plasma membrane / astrocyte activation / NOTCH3 Activation and Transmission of Signal to the Nucleus / cellular response to amino acid stimulus / positive regulation of smooth muscle cell proliferation / cellular response to estradiol stimulus / lung development / cell surface receptor protein tyrosine kinase signaling pathway / EGFR downregulation / synaptic membrane / Signaling by ERBB2 TMD/JMD mutants / clathrin-coated endocytic vesicle membrane / placental growth factor receptor activity / insulin receptor activity / vascular endothelial growth factor receptor activity / Constitutive Signaling by EGFRvIII / hepatocyte growth factor receptor activity / macrophage colony-stimulating factor receptor activity / platelet-derived growth factor alpha-receptor activity / platelet-derived growth factor beta-receptor activity / stem cell factor receptor activity / boss receptor activity / protein tyrosine kinase collagen receptor activity / brain-derived neurotrophic factor receptor activity / transmembrane-ephrin receptor activity / GPI-linked ephrin receptor activity
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
: / IODIDE ION / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.435 Å
AuthorsHargreaves, D.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2024
Title: Optimization of Potent, Efficacious, Selective and Blood-Brain Barrier Penetrating Inhibitors Targeting EGFR Exon20 Insertion Mutations.
Authors: Thomson, C. / Braybrooke, E. / Colclough, N. / Davies, N.L. / Floc'h, N. / Greenwood, R. / Guerot, C. / Hargreaves, D. / Johnstrom, P. / Khurana, P. / Kostomiris, D.H. / Li, S. / Lister, A. ...Authors: Thomson, C. / Braybrooke, E. / Colclough, N. / Davies, N.L. / Floc'h, N. / Greenwood, R. / Guerot, C. / Hargreaves, D. / Johnstrom, P. / Khurana, P. / Kostomiris, D.H. / Li, S. / Lister, A. / Lorthioir, O. / Martin, S. / McCoull, W. / McLean, N.J. / McWilliams, L. / Orme, J.P. / Packer, M.J. / Pearson, S. / Swaih, A.M. / Tentarelli, S. / Tucker, M.J. / Ward, R.A. / Wilkinson, S. / Winlow, P. / Wood, I.L.
History
DepositionApr 4, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 6, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,09917
Polymers37,7751
Non-polymers2,32416
Water50428
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2260 Å2
ΔGint-5 kcal/mol
Surface area12720 Å2
Unit cell
Length a, b, c (Å)91.561, 105.019, 84.254
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number20
Space group name H-MC2221

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Components

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


Mass: 37774.594 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-A1H7N / 1-[3-pyridin-4-yl-2-[3-(2-pyrimidin-2-ylethynyl)phenyl]-4,6-dihydropyrrolo[3,4-d]imidazol-5-yl]propan-1-one


Mass: 420.466 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H20N6O / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-IOD / IODIDE ION


Mass: 126.904 Da / Num. of mol.: 15 / Source method: obtained synthetically / Formula: I
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 28 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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: 2.68 Å3/Da / Density % sol: 54.12 % / Description: very thin plates
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: 17 % PEG8000, 0.2 M NH4I, 0.1 M PCTP pH 7.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.97625 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jul 20, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97625 Å / Relative weight: 1
ReflectionResolution: 2.435→53.39 Å / Num. obs: 5401 / % possible obs: 85.1 % / Redundancy: 9.9 % / CC1/2: 0.997 / Net I/σ(I): 6.4
Reflection shellResolution: 2.435→2.857 Å / Num. unique obs: 271 / CC1/2: 0.471

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Processing

Software
NameVersionClassification
BUSTER2.11.8 (26-JUL-2023)refinement
MOSFLMdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.435→53.39 Å / Cor.coef. Fo:Fc: 0.857 / Cor.coef. Fo:Fc free: 0.736 / Cross valid method: THROUGHOUT / σ(F): 0 / SU Rfree Blow DPI: 0.717
RfactorNum. reflection% reflectionSelection details
Rfree0.3255 280 5.23 %RANDOM
Rwork0.2251 ---
obs0.2303 5358 34.4 %-
Displacement parametersBiso mean: 38.68 Å2
Baniso -1Baniso -2Baniso -3
1--13.2518 Å20 Å20 Å2
2--7.4343 Å20 Å2
3---5.8176 Å2
Refine analyzeLuzzati coordinate error obs: 0.53 Å
Refinement stepCycle: LAST / Resolution: 2.435→53.39 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2178 0 47 28 2253
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0072262HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.933064HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d800SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes398HARMONIC5
X-RAY DIFFRACTIONt_it2262HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.67
X-RAY DIFFRACTIONt_other_torsion21.59
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion292SEMIHARMONIC5
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_contact1872SEMIHARMONIC4
LS refinement shellResolution: 2.44→2.94 Å / Total num. of bins used: 15
RfactorNum. reflection% reflection
Rfree0.3633 -4.7 %
Rwork0.2139 365 -
all0.2207 383 -
obs--5.75 %

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