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- PDB-9s3x: EGFR (T790M,L858R) in complex with NCL-26007 -

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Basic information

Entry
Database: PDB / ID: 9s3x
TitleEGFR (T790M,L858R) in complex with NCL-26007
ComponentsEpidermal growth factor receptor
KeywordsTRANSFERASE / EGFR / covalent
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 / PLCG1 events in ERBB2 signaling / ERBB2-EGFR signaling pathway / morphogenesis of an epithelial fold / PTK6 promotes HIF1A stabilization / Signaling by EGFR / ERBB2 Activates PTK6 Signaling / digestive tract morphogenesis / 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 / positive regulation of G1/S transition of mitotic cell cycle / GAB1 signalosome / embryonic placenta development / salivary gland morphogenesis / 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 / ossification / basal plasma membrane / cellular response to epidermal growth factor stimulus / positive regulation of DNA repair / positive regulation of DNA replication / epithelial cell proliferation / positive regulation of epithelial cell proliferation / Signal transduction by L1 / positive regulation of protein localization to plasma membrane / cellular response to amino acid stimulus / phosphatidylinositol 3-kinase/protein kinase B signal transduction / NOTCH3 Activation and Transmission of Signal to the Nucleus / cellular response to estradiol stimulus / clathrin-coated endocytic vesicle membrane / EGFR downregulation / Signaling by ERBB2 TMD/JMD mutants / cell-cell adhesion / Constitutive Signaling by EGFRvIII / receptor protein-tyrosine kinase / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / negative regulation of protein catabolic process / positive regulation of miRNA transcription / epidermal growth factor receptor signaling pathway / kinase binding / ruffle membrane / Downregulation of ERBB2 signaling / positive regulation of fibroblast proliferation / cell morphogenesis / neuron differentiation / positive regulation of protein phosphorylation / 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 / 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 / double-stranded DNA binding / early endosome membrane / protein phosphatase binding / nuclear membrane / basolateral plasma membrane / learning or memory / cell surface receptor signaling pathway / Extra-nuclear estrogen signaling / positive regulation of ERK1 and ERK2 cascade
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: 2.423 Å
AuthorsMartin, M.P. / Pintar, S. / Noble, M.E.M.
Funding support United Kingdom, 2items
OrganizationGrant numberCountry
Cancer Research UKDRCDDRPGMApr2020 United Kingdom
Medical Research Council (MRC, United Kingdom)MR/X004872/1 United Kingdom
CitationJournal: J.Med.Chem. / Year: 2026
Title: Covalent Alkynylpyridopyrimidinones Targeting Cysteine 775 of the Epidermal Growth Factor Receptor Overcome Resistance to Current Therapies.
Authors: Stewart, H.L. / Bordoni, C. / Jennings, C.E. / Al-Khawaldeh, I. / Martin, M.P. / Noble, R.A. / Phillips, N. / Pintar, S. / Prendergast, L. / Thomas, H.D. / Wang, L.Z. / Watt, J.E. / Wittner, ...Authors: Stewart, H.L. / Bordoni, C. / Jennings, C.E. / Al-Khawaldeh, I. / Martin, M.P. / Noble, R.A. / Phillips, N. / Pintar, S. / Prendergast, L. / Thomas, H.D. / Wang, L.Z. / Watt, J.E. / Wittner, A. / Bronowska, A.K. / Cano, C. / Noble, M.E.M. / Wedge, S.R. / Waring, M.J.
History
DepositionJul 25, 2025Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 14, 2026Provider: repository / Type: Initial release
Revision 1.1Jan 21, 2026Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year / _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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,3152
Polymers36,8751
Non-polymers4411
Water3,801211
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area15920 Å2
Unit cell
Length a, b, c (Å)143.18, 143.18, 143.18
Angle α, β, γ (deg.)90, 90, 90
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: 36874.711 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: unidentified baculovirus
References: UniProt: P00533, receptor protein-tyrosine kinase
#2: Chemical ChemComp-A1JLU / 2-[[4-[2-(dimethylamino)ethyl-methyl-amino]phenyl]amino]-5-ethenyl-8-phenyl-pyrido[2,3-d]pyrimidin-7-one


Mass: 440.540 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H28N6O
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 211 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestN
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: 3.32 Å3/Da / Density % sol: 62.9 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: 0.15M Sodium Citrate, 0.1M TRIS pH8.5, 25% PEG400

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Data collection

DiffractionMean temperature: 173 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.89842 Å
DetectorType: DECTRIS EIGER2 XE 16M / Detector: PIXEL / Date: Nov 8, 2024
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.89842 Å / Relative weight: 1
ReflectionResolution: 2.4→50.62 Å / Num. obs: 19240 / % possible obs: 100 % / Redundancy: 41.3 % / CC1/2: 1 / Rmerge(I) obs: 0.169 / Rpim(I) all: 0.037 / Rrim(I) all: 0.173 / Χ2: 1.01 / Net I/σ(I): 16.7
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
8.98-50.6239.50.0471.340910.0090.0410.7799.5
2.4-2.4942.85.9980.819990.5641.316.140.88100

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Processing

Software
NameVersionClassification
REFMAC5.8.0430 (refmacat 0.4.82)refinement
REFMAC5.8.0430 (refmacat 0.4.82)refinement
Aimlessdata scaling
pointlessdata scaling
PHASERphasing
xia2data reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.423→50.62 Å / Cor.coef. Fo:Fc: 0.965 / Cor.coef. Fo:Fc free: 0.947 / WRfactor Rfree: 0.252 / WRfactor Rwork: 0.184 / SU B: 9.325 / SU ML: 0.2 / Average fsc free: 0.9298 / Average fsc work: 0.9476 / Cross valid method: FREE R-VALUE / ESU R: 0.317 / ESU R Free: 0.245 / Details: Hydrogens have not been used
RfactorNum. reflection% reflection
Rfree0.2461 952 5.14 %
Rwork0.1892 17568 -
all0.192 --
obs-18520 99.075 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT
Displacement parametersBiso mean: 84.954 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å20 Å20 Å2
2--0 Å20 Å2
3---0 Å2
Refinement stepCycle: LAST / Resolution: 2.423→50.62 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2585 0 33 211 2829
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0122696
X-RAY DIFFRACTIONr_angle_refined_deg1.7221.8343653
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.4425327
X-RAY DIFFRACTIONr_dihedral_angle_2_deg13.986524
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.00710485
X-RAY DIFFRACTIONr_dihedral_angle_6_deg14.51510115
X-RAY DIFFRACTIONr_chiral_restr0.1150.2400
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.022043
X-RAY DIFFRACTIONr_nbd_refined0.2130.21291
X-RAY DIFFRACTIONr_nbtor_refined0.3160.21789
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.210.2181
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.2360.2124
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.1790.233
X-RAY DIFFRACTIONr_mcbond_it7.8298.3061305
X-RAY DIFFRACTIONr_mcangle_it11.44814.9031633
X-RAY DIFFRACTIONr_scbond_it10.1928.6241391
X-RAY DIFFRACTIONr_scangle_it14.64715.6112020
X-RAY DIFFRACTIONr_lrange_it20.217103.69312481
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 20

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRfactor allNum. reflection allFsc freeFsc work% reflection obs (%)WRfactor Rwork
2.423-2.4861.56681.45110851.45713230.6470.56387.15041.555
2.486-2.5540.698800.53912870.54713670.8860.9141000.548
2.554-2.6270.399710.31312070.31712780.9270.9561000.31
2.627-2.7080.297520.24812080.2512600.9460.9641000.238
2.708-2.7970.288620.22411590.22712210.9450.9691000.209
2.797-2.8940.241480.19211440.19411920.9690.9771000.174
2.894-3.0030.227550.16910940.17211490.970.9831000.148
3.003-3.1250.274690.17310170.17810860.960.9821000.152
3.125-3.2640.325630.17610030.18410660.9280.9821000.156
3.264-3.4220.217460.1749450.1769910.9670.9821000.157
3.422-3.6070.285410.1749320.1799730.9520.9841000.161
3.607-3.8240.209340.1598850.1619190.9740.9861000.15
3.824-4.0870.151360.168220.1598580.9860.9871000.154
4.087-4.4120.182550.1767590.1768140.9810.9831000.172
4.412-4.8290.194350.1427050.1447400.9750.9891000.142
4.829-5.3930.216470.1466370.156840.9740.9871000.145
5.393-6.2160.25310.1895600.1925910.9650.9821000.188
6.216-7.5840.353340.2034810.2135150.9410.9781000.207
7.584-10.6070.154130.1583950.1584080.9790.9861000.182
10.607-50.620.289120.272430.2712550.9540.9551000.309

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