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- PDB-9gc6: Highly optimized CNS penetrant inhibitors of EGFR Exon20 Insertio... -

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Basic information

Entry
Database: PDB / ID: 9gc6
TitleHighly optimized CNS penetrant inhibitors of EGFR Exon20 Insertion Mutations
ComponentsEpidermal growth factor receptor
KeywordsSIGNALING PROTEIN / EGFR / Exon20 / NPG
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 / EGFR interacts with phospholipase C-gamma / epidermal growth factor receptor activity / 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 / EGFR interacts with phospholipase C-gamma / epidermal growth factor receptor activity / regulation of peptidyl-tyrosine phosphorylation / epidermal growth factor binding / response to UV-A / PLCG1 events in ERBB2 signaling / ERBB2-EGFR signaling pathway / morphogenesis of an epithelial fold / PTK6 promotes HIF1A stabilization / ERBB2 Activates PTK6 Signaling / digestive tract morphogenesis / Signaling by EGFR / intracellular vesicle / eyelid development in camera-type eye / negative regulation of epidermal growth factor receptor signaling pathway / cerebral cortex cell migration / protein insertion into membrane / ERBB2 Regulates Cell Motility / protein tyrosine kinase activator activity / Respiratory syncytial virus (RSV) attachment and entry / Signaling by ERBB4 / PI3K events in ERBB2 signaling / positive regulation of phosphorylation / positive regulation of peptidyl-serine phosphorylation / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / hair follicle development / MAP kinase kinase kinase activity / GAB1 signalosome / positive regulation of G1/S transition of mitotic cell cycle / embryonic placenta development / salivary gland morphogenesis / Signaling by ERBB2 / GRB2 events in EGFR signaling / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / SHC1 events in EGFR signaling / transmembrane receptor protein tyrosine kinase activity / EGFR Transactivation by Gastrin / GRB2 events in ERBB2 signaling / SHC1 events in ERBB2 signaling / ossification / NOTCH3 Activation and Transmission of Signal to the Nucleus / positive regulation of DNA repair / basal plasma membrane / cellular response to epidermal growth factor stimulus / EGFR downregulation / positive regulation of DNA replication / epithelial cell proliferation / Signal transduction by L1 / positive regulation of epithelial cell proliferation / positive regulation of protein localization to plasma membrane / cellular response to amino acid stimulus / phosphatidylinositol 3-kinase/protein kinase B signal transduction / cellular response to estradiol stimulus / clathrin-coated endocytic vesicle membrane / Signaling by ERBB2 TMD/JMD mutants / Constitutive Signaling by EGFRvIII / Downregulation of ERBB2 signaling / cell-cell adhesion / receptor protein-tyrosine kinase / negative regulation of protein catabolic process / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / positive regulation of miRNA transcription / kinase binding / ruffle membrane / positive regulation of protein phosphorylation / epidermal growth factor receptor signaling pathway / neuron differentiation / cell morphogenesis / positive regulation of fibroblast proliferation / HCMV Early Events / Constitutive Signaling by Aberrant PI3K in Cancer / actin filament binding / Cargo recognition for clathrin-mediated endocytosis / cell junction / transmembrane signaling receptor activity / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / positive regulation of canonical Wnt signaling pathway / Clathrin-mediated endocytosis / PIP3 activates AKT signaling / virus receptor activity / ATPase binding / RAF/MAP kinase cascade / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / positive regulation of cell growth / double-stranded DNA binding / protein tyrosine kinase activity / early endosome membrane / protein phosphatase binding / nuclear membrane / basolateral plasma membrane / learning or memory / Extra-nuclear estrogen signaling / cell surface receptor signaling pathway / 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 / 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
: / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.901 Å
AuthorsHargreaves, D.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2025
Title: Highly Optimized CNS Penetrant Inhibitors of EGFR Exon20 Insertion Mutations.
Authors: McCoull, W. / Thomson, C. / Braybrooke, E. / Chan, C. / Colclough, N. / Cortes Gonzalez, M.A. / Cosulich, S. / Davies, N.L. / Floc'h, N. / Greenwood, R. / Hargreaves, D. / Huang, P. / Hunt, ...Authors: McCoull, W. / Thomson, C. / Braybrooke, E. / Chan, C. / Colclough, N. / Cortes Gonzalez, M.A. / Cosulich, S. / Davies, N.L. / Floc'h, N. / Greenwood, R. / Hargreaves, D. / Huang, P. / Hunt, T.A. / Johnson, T. / Johnstrom, P. / Kettle, J.G. / Kondrashov, M. / Kostomiris, D.H. / Li, S. / Lister, A. / Martin, S. / McKerrecher, D. / McLean, N. / Nissink, J.W.M. / Orme, J.P. / Orwig, P. / Packer, M.J. / Pearson, S. / Qin, L. / Felisberto-Rodrigues, C. / Savoca, A. / Schou, M. / Stokes, S. / Swaih, A.M. / Talbot, S. / Tucker, M.J. / Ward, R.A. / Wadforth, E. / Wang, C. / Wilson, J. / Yang, Y.
History
DepositionAug 1, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 12, 2025Provider: repository / Type: Initial release
Revision 1.1Feb 26, 2025Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Epidermal growth factor receptor
B: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)76,0524
Polymers75,1872
Non-polymers8652
Water3,027168
1
A: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,0262
Polymers37,5931
Non-polymers4321
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,0262
Polymers37,5931
Non-polymers4321
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)76.435, 70.934, 78.230
Angle α, β, γ (deg.)90.00, 112.88, 90.00
Int Tables number4
Space group name H-MP1211

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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.: 2
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-A1IZ9 / 1-[2-[5-fluoranyl-4-(2-fluorophenyl)pyridin-2-yl]-3-pyrimidin-4-yl-4,6-dihydropyrrolo[3,4-d]imidazol-5-yl]propan-1-one


Mass: 432.425 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H18F2N6O / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 168 / 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: 2.6 Å3/Da / Density % sol: 52.67 % / Description: rod like
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: Peg 8K

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.9795 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Feb 25, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 1.901→72.073 Å / Num. obs: 33926 / % possible obs: 90.1 % / Redundancy: 5.2 % / CC1/2: 0.998 / Net I/σ(I): 7.5
Reflection shellResolution: 1.901→2.154 Å / Num. unique obs: 1697 / CC1/2: 0.729

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Processing

Software
NameVersionClassification
autoPROCdata reduction
STARANISOdata scaling
BUSTER2.11.8 (26-JUL-2023)refinement
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.901→64.42 Å / Cor.coef. Fo:Fc: 0.916 / Cor.coef. Fo:Fc free: 0.882 / SU R Cruickshank DPI: 0.373 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.362 / SU Rfree Blow DPI: 0.281 / SU Rfree Cruickshank DPI: 0.287
RfactorNum. reflection% reflectionSelection details
Rfree0.3228 1678 4.96 %RANDOM
Rwork0.2662 ---
obs0.269 33819 55.7 %-
Displacement parametersBiso mean: 29.59 Å2
Baniso -1Baniso -2Baniso -3
1--0.0873 Å20 Å20.359 Å2
2--0.1224 Å20 Å2
3----0.0351 Å2
Refine analyzeLuzzati coordinate error obs: 0.37 Å
Refinement stepCycle: LAST / Resolution: 1.901→64.42 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4815 0 64 168 5047
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0084991HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.946754HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1771SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes880HARMONIC5
X-RAY DIFFRACTIONt_it4991HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.96
X-RAY DIFFRACTIONt_other_torsion18.42
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion640SEMIHARMONIC5
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_contact3992SEMIHARMONIC4
LS refinement shellResolution: 1.901→2.06 Å
RfactorNum. reflection% reflection
Rfree0.3658 -5.02 %
Rwork0.3556 643 -
obs--5.19 %

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