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- PDB-9gc4: Highly optimized CNS penetrant inhibitors of EGFR Exon20 Insertio... -

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Basic information

Entry
Database: PDB / ID: 9gc4
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


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 / regulation of peptidyl-tyrosine phosphorylation / response to UV-A / tongue development / PLCG1 events in ERBB2 signaling / midgut development / ERBB2-EGFR signaling pathway / digestive tract morphogenesis / hydrogen peroxide metabolic process / morphogenesis of an epithelial fold / PTK6 promotes HIF1A stabilization / 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 / protein tyrosine kinase activator activity / Signaling by ERBB4 / Respiratory syncytial virus (RSV) attachment and entry / 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 / positive regulation of bone resorption / embryonic placenta development / positive regulation of phosphorylation / salivary gland morphogenesis / peptidyl-tyrosine autophosphorylation / positive regulation of peptidyl-serine phosphorylation / 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 / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / GRB2 events in ERBB2 signaling / SHC1 events in ERBB2 signaling / cellular response to epidermal growth factor stimulus / cellular response to dexamethasone stimulus / positive regulation of synaptic transmission, glutamatergic / ossification / positive regulation of DNA repair / neuron projection morphogenesis / positive regulation of superoxide anion generation / positive regulation of epithelial cell proliferation / liver regeneration / epithelial cell proliferation / basal plasma membrane / Signal transduction by L1 / positive regulation of DNA replication / positive regulation of protein localization to plasma membrane / astrocyte activation / phosphatidylinositol 3-kinase/protein kinase B signal transduction / 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 / 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 / epidermal growth factor receptor activity / fibroblast growth factor receptor activity / insulin-like growth factor receptor activity / Signaling by ERBB2 ECD mutants
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: 2.415 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
D: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)114,2545
Polymers113,3243
Non-polymers9302
Water3,513195
1
A: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,2392
Polymers37,7751
Non-polymers4651
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area13670 Å2
MethodPISA
2
B: Epidermal growth factor receptor
D: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)76,0143
Polymers75,5492
Non-polymers4651
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1440 Å2
ΔGint-3 kcal/mol
Surface area14430 Å2
MethodPISA
Unit cell
Length a, b, c (Å)134.524, 84.246, 96.465
Angle α, β, γ (deg.)90.00, 121.29, 90.00
Int Tables number5
Space group name H-MC121

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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.: 3
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-A1IZ7 / 1-[2-[3-(3-chloranyl-6-fluoranyl-pyridin-2-yl)oxyphenyl]-3-pyrimidin-4-yl-4,6-dihydropyrrolo[3,4-d]imidazol-5-yl]propan-1-one


Mass: 464.879 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H18ClFN6O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 195 / 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: 2.06 Å3/Da / Density % sol: 40.32 % / Description: plate like
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: alcohols 10%, MB1 0.1M pH 6.5, EDO_P8K 30%w/v (morpheus screen D2)

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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: Oct 21, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 2.415→65.85 Å / Num. obs: 23451 / % possible obs: 78 % / Redundancy: 3.4 % / CC1/2: 0.996 / Net I/σ(I): 6.6
Reflection shellResolution: 2.415→2.633 Å / Num. unique obs: 1173 / CC1/2: 0.655

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Processing

Software
NameVersionClassification
MOSFLMdata reduction
Aimlessdata scaling
BUSTER2.11.8 (26-JUL-2023)refinement
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.415→26.91 Å / Cor.coef. Fo:Fc: 0.921 / Cor.coef. Fo:Fc free: 0.897 / SU R Cruickshank DPI: 0.704 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.685 / SU Rfree Blow DPI: 0.309 / SU Rfree Cruickshank DPI: 0.315
RfactorNum. reflection% reflectionSelection details
Rfree0.2481 1139 4.86 %RANDOM
Rwork0.2165 ---
obs0.218 23425 66.2 %-
Displacement parametersBiso mean: 53.45 Å2
Baniso -1Baniso -2Baniso -3
1-0.3377 Å20 Å20.4414 Å2
2--0.1402 Å20 Å2
3----0.4779 Å2
Refine analyzeLuzzati coordinate error obs: 0.36 Å
Refinement stepCycle: LAST / Resolution: 2.415→26.91 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4702 0 66 195 4963
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0074880HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.916602HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1735SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes798HARMONIC5
X-RAY DIFFRACTIONt_it4880HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.81
X-RAY DIFFRACTIONt_other_torsion19.95
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion622SEMIHARMONIC5
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_contact3876SEMIHARMONIC4
LS refinement shellResolution: 2.42→2.55 Å / Total num. of bins used: 51
RfactorNum. reflection% reflection
Rfree0.2483 -3.84 %
Rwork0.2832 451 -
all0.2819 469 -
obs--8.81 %

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