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- PDB-8po3: Discovery and Optimisation of Potent, Efficacious and Selective I... -

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Basic information

Entry
Database: PDB / ID: 8po3
TitleDiscovery and Optimisation of Potent, Efficacious and Selective Inhibitors Targeting EGFR Exon20 Insertion Mutations. Compound 18 bound to EGFR[V948R]
ComponentsEpidermal growth factor receptor
KeywordsSIGNALING PROTEIN / EGFR / Exon 20 insertion / non-small cell lung cancer / oncology
Function / homology
Function and homology information


multivesicular body, internal vesicle lumen / negative regulation of cardiocyte differentiation / Shc-EGFR complex / positive regulation of protein kinase C signaling / Inhibition of Signaling by Overexpressed EGFR / epidermal growth factor receptor activity / EGFR interacts with phospholipase C-gamma / regulation of peptidyl-tyrosine phosphorylation / epidermal growth factor binding / response to UV-A ...multivesicular body, internal vesicle lumen / negative regulation of cardiocyte differentiation / Shc-EGFR complex / positive regulation of protein kinase C signaling / Inhibition of Signaling by Overexpressed EGFR / epidermal growth factor receptor activity / EGFR interacts with phospholipase C-gamma / regulation of peptidyl-tyrosine phosphorylation / epidermal growth factor binding / response to UV-A / ubiquitin-dependent endocytosis / PLCG1 events in ERBB2 signaling / morphogenesis of an epithelial fold / PTK6 promotes HIF1A stabilization / ERBB2 Activates PTK6 Signaling / digestive tract morphogenesis / ERBB2-EGFR signaling pathway / Signaling by EGFR / eyelid development in camera-type eye / cerebral cortex cell migration / intracellular vesicle / Developmental Lineage of Mammary Gland Myoepithelial Cells / ERBB2 Regulates Cell Motility / protein insertion into membrane / Respiratory syncytial virus (RSV) attachment and entry / protein tyrosine kinase activator activity / Signaling by ERBB4 / negative regulation of epidermal growth factor receptor signaling pathway / PI3K events in ERBB2 signaling / positive regulation of peptidyl-serine phosphorylation / positive regulation of phosphorylation / hair follicle development / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / MAP kinase kinase kinase activity / GAB1 signalosome / embryonic placenta development / positive regulation of G1/S transition of mitotic cell cycle / salivary gland morphogenesis / xenobiotic transport / positive regulation of epidermal growth factor receptor signaling pathway / Signaling by ERBB2 / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / GRB2 events in EGFR signaling / transmembrane receptor protein tyrosine kinase activity / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / GRB2 events in ERBB2 signaling / SHC1 events in ERBB2 signaling / epithelial cell proliferation / ossification / cellular response to epidermal growth factor stimulus / basal plasma membrane / positive regulation of DNA replication / positive regulation of epithelial cell proliferation / positive regulation of DNA repair / Signal transduction by L1 / positive regulation of protein localization to plasma membrane / sperm end piece / cellular response to estradiol stimulus / NOTCH3 Activation and Transmission of Signal to the Nucleus / cellular response to amino acid stimulus / phosphatidylinositol 3-kinase/protein kinase B signal transduction / clathrin-coated endocytic vesicle membrane / EGFR downregulation / Signaling by ERBB2 TMD/JMD mutants / Constitutive Signaling by EGFRvIII / receptor protein-tyrosine kinase / Signaling by ERBB2 ECD mutants / cell-cell adhesion / negative regulation of protein catabolic process / Signaling by ERBB2 KD Mutants / positive regulation of protein phosphorylation / positive regulation of miRNA transcription / Downregulation of ERBB2 signaling / kinase binding / positive regulation of fibroblast proliferation / ruffle membrane / epidermal growth factor receptor signaling pathway / cell morphogenesis / neuron differentiation / Constitutive Signaling by Aberrant PI3K in Cancer / HCMV Early Events / actin filament binding / cell junction / transmembrane signaling receptor activity / positive regulation of canonical Wnt signaling pathway / PIP3 activates AKT signaling / Cargo recognition for clathrin-mediated endocytosis / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / Clathrin-mediated endocytosis / sperm principal piece / ATPase binding / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / virus receptor activity / RAF/MAP kinase cascade / positive regulation of cell growth / protein tyrosine kinase activity / sperm midpiece / double-stranded DNA binding / early endosome 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
: / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.13 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
Revision 1.2Nov 6, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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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)38,1152
Polymers37,5931
Non-polymers5221
Water4,035224
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 area14250 Å2
MethodPISA
Unit cell
Length a, b, c (Å)110.000, 84.360, 34.760
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP21212

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Components

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


Mass: 37593.402 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 ascovirus 1d
References: UniProt: P00533, receptor protein-tyrosine kinase
#2: Chemical ChemComp-2II / 2-methyl-5-[[3-[1-[(3~{S})-1-propanoylpyrrolidin-3-yl]-4-pyridin-4-yl-pyrazol-3-yl]phenoxy]methyl]-3~{H}-isoindol-1-one


Mass: 521.610 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C31H31N5O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 224 / 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: 2.15 Å3/Da / Density % sol: 42.66 % / Description: small plate-like crystals
Crystal growTemperature: 293.15 K / Method: vapor diffusion, sitting drop / Details: PEG 8K 12%w/v pH 0, PCPT 0.1M pH 5.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.91587 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Oct 13, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.91587 Å / Relative weight: 1
ReflectionResolution: 1.805→110.171 Å / Num. obs: 159456 / % possible obs: 93.3 % / Redundancy: 5.8 % / CC1/2: 0.995 / Net I/σ(I): 7.4
Reflection shellResolution: 1.805→1.836 Å / Num. unique obs: 77 / CC1/2: 0.484

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Processing

Software
NameVersionClassification
MOSFLMdata reduction
Aimlessdata scaling
BUSTER2.11.8 (24-FEB-2021)refinement
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.13→42.18 Å / Cor.coef. Fo:Fc: 0.912 / Cor.coef. Fo:Fc free: 0.867 / SU R Cruickshank DPI: 0.251 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.283 / SU Rfree Blow DPI: 0.218 / SU Rfree Cruickshank DPI: 0.21
RfactorNum. reflection% reflectionSelection details
Rfree0.2688 938 5.01 %RANDOM
Rwork0.2191 ---
obs0.2217 18712 99.3 %-
Displacement parametersBiso mean: 23.67 Å2
Baniso -1Baniso -2Baniso -3
1--1.2332 Å20 Å20 Å2
2--1.6554 Å20 Å2
3----0.4223 Å2
Refine analyzeLuzzati coordinate error obs: 0.28 Å
Refinement stepCycle: LAST / Resolution: 2.13→42.18 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2246 0 39 224 2509
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0082345HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.963174HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d836SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes380HARMONIC5
X-RAY DIFFRACTIONt_it2345HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.21
X-RAY DIFFRACTIONt_other_torsion17.5
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion303SEMIHARMONIC5
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_contact2156SEMIHARMONIC4
LS refinement shellResolution: 2.13→2.15 Å / Total num. of bins used: 47
RfactorNum. reflection% reflection
Rfree0.3168 -5.41 %
Rwork0.2611 385 -
all0.2643 407 -
obs--99.75 %

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