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Basic information

Entry
Database: PDB / ID: 8po0
TitleDiscovery and Optimisation of Potent, Efficacious and Selective Inhibitors Targeting EGFR Exon20 Insertion Mutations. Compound 12 bound to EGFRinsNPG
ComponentsEpidermal growth factor receptor
KeywordsSIGNALING PROTEIN / EGFR / Exon 20 insertion / non-small cell lung cancer / oncology
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 / 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 / Respiratory syncytial virus (RSV) attachment and entry / 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 / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / MAP kinase kinase kinase activity / embryonic placenta development / positive regulation of bone resorption / positive regulation of G1/S transition of mitotic cell cycle / GAB1 signalosome / 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 / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / cellular response to cadmium ion / 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 / positive regulation of synaptic transmission, glutamatergic / ossification / cellular response to dexamethasone stimulus / basal plasma membrane / neurogenesis / regulation of ERK1 and ERK2 cascade / neuron projection morphogenesis / positive regulation of superoxide anion generation / positive regulation of DNA replication / epithelial cell proliferation / Signal transduction by L1 / 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 / 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 / lung development / clathrin-coated endocytic vesicle membrane / Constitutive Signaling by EGFRvIII / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / epidermal growth factor receptor signaling pathway / negative regulation of protein catabolic process / receptor protein-tyrosine kinase / Downregulation of ERBB2 signaling / kinase binding / ruffle membrane / positive regulation of miRNA transcription / cell-cell adhesion
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
: / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.523 Å
AuthorsHargreaves, D.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2024
Title: Discovery and Optimization of Potent, Efficacious and Selective Inhibitors Targeting EGFR Exon20 Insertion Mutations.
Authors: Thomson, C. / Barton, P. / Braybrooke, E. / Colclough, N. / Dong, Z. / Evans, L. / Floc'h, N. / Guerot, C. / Hargreaves, D. / Khurana, P. / Li, S. / Li, X. / Lister, A. / McCoull, W. / ...Authors: Thomson, C. / Barton, P. / Braybrooke, E. / Colclough, N. / Dong, Z. / Evans, L. / Floc'h, N. / Guerot, C. / Hargreaves, D. / Khurana, P. / Li, S. / Li, X. / Lister, A. / McCoull, W. / McWilliams, L. / Orme, J.P. / Packer, M.J. / Swaih, A.M. / Ward, R.A. / Winlow, P. / Ye, Y.
History
DepositionJul 3, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 5, 2024Provider: repository / Type: Initial release
Revision 1.1Jun 19, 2024Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last

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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)38,1762
Polymers37,7171
Non-polymers4591
Water543
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 area16850 Å2
MethodPISA
Unit cell
Length a, b, c (Å)150.769, 150.769, 150.769
Angle α, β, γ (deg.)90.00, 90.00, 90.00
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: 37716.527 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-2I6 / 1-[3-[7-methoxy-4-[3-(3-methoxyphenyl)-1~{H}-pyrazol-4-yl]quinazolin-6-yl]oxyazetidin-1-yl]propan-1-one


Mass: 459.497 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H25N5O4 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 3 / 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: 3.79 Å3/Da / Density % sol: 67.51 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion, sitting drop / Details: Sodium Citrate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID14-1 / Wavelength: 0.99 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Oct 27, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99 Å / Relative weight: 1
ReflectionResolution: 1→47.68 Å / Num. obs: 19264 / % possible obs: 100 % / Redundancy: 1 % / CC1/2: 1 / Net I/σ(I): 1
Reflection shellResolution: 1→1 Å / Num. unique obs: 1 / CC1/2: 0.5

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Processing

Software
NameVersionClassification
autoPROCdata reduction
autoPROCdata scaling
BUSTER2.11.8 (24-FEB-2021)refinement
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.523→47.68 Å / Cor.coef. Fo:Fc: 0.93 / Cor.coef. Fo:Fc free: 0.879 / SU R Cruickshank DPI: 0.413 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.394 / SU Rfree Blow DPI: 0.33 / SU Rfree Cruickshank DPI: 0.341
RfactorNum. reflection% reflectionSelection details
Rfree0.3755 989 5.13 %RANDOM
Rwork0.3151 ---
obs0.3182 19264 99.6 %-
Displacement parametersBiso mean: 96.52 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å20 Å20 Å2
2--0 Å20 Å2
3---0 Å2
Refine analyzeLuzzati coordinate error obs: 0.64 Å
Refinement stepCycle: LAST / Resolution: 2.523→47.68 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2466 0 34 3 2503
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0092557HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.033461HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d902SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes451HARMONIC5
X-RAY DIFFRACTIONt_it2557HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.99
X-RAY DIFFRACTIONt_other_torsion21.43
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion326SEMIHARMONIC5
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_contact1861SEMIHARMONIC4
LS refinement shellResolution: 2.523→2.54 Å
RfactorNum. reflection% reflection
Rfree0.4306 -6.85 %
Rwork0.4817 367 -
obs--84.57 %

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