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- PDB-8f1y: EGFR kinase in complex with poziotinib -

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Basic information

Entry
Database: PDB / ID: 8f1y
TitleEGFR kinase in complex with poziotinib
ComponentsEpidermal growth factor receptor
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / EGFR / kinase / inhibitor / TRANSFERASE / TRANSFERASE-TRANSFERASE INHIBITOR complex
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 / ERBB2 Activates PTK6 Signaling / digestive tract morphogenesis / Signaling by EGFR / intracellular vesicle / 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 / 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 / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / transmembrane receptor protein tyrosine kinase activity / EGFR Transactivation by Gastrin / GRB2 events in ERBB2 signaling / ossification / SHC1 events in ERBB2 signaling / basal plasma membrane / positive regulation of DNA repair / cellular response to epidermal growth factor stimulus / 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 / NOTCH3 Activation and Transmission of Signal to the Nucleus / cellular response to amino acid stimulus / phosphatidylinositol 3-kinase/protein kinase B signal transduction / cellular response to estradiol stimulus / EGFR downregulation / clathrin-coated endocytic vesicle membrane / Signaling by ERBB2 TMD/JMD mutants / Constitutive Signaling by EGFRvIII / cell-cell adhesion / receptor protein-tyrosine kinase / Signaling by ERBB2 ECD mutants / negative regulation of protein catabolic process / Signaling by ERBB2 KD Mutants / positive regulation of miRNA transcription / kinase binding / ruffle membrane / Downregulation of ERBB2 signaling / epidermal growth factor receptor signaling pathway / positive regulation of protein phosphorylation / positive regulation of fibroblast proliferation / cell morphogenesis / neuron differentiation / HCMV Early Events / Constitutive Signaling by Aberrant PI3K in Cancer / actin filament binding / cell junction / transmembrane signaling receptor activity / positive regulation of canonical Wnt signaling pathway / Cargo recognition for clathrin-mediated endocytosis / PIP3 activates AKT signaling / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / Clathrin-mediated endocytosis / virus receptor activity / ATPase binding / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / RAF/MAP kinase cascade / 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 / 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
CITRIC ACID / Chem-R2E / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.75 Å
AuthorsBeyett, T.S. / Eck, M.J.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)5R01CA116020-16 United States
CitationJournal: Proc.Natl.Acad.Sci.USA / Year: 2024
Title: Biochemical analysis of EGFR exon20 insertion variants insASV and insSVD and their inhibitor sensitivity.
Authors: Zhao, H. / Beyett, T.S. / Jiang, J. / Rana, J.K. / Schaeffner, I.K. / Santana, J. / Janne, P.A. / Eck, M.J.
History
DepositionNov 6, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 8, 2023Provider: repository / Type: Initial release
Revision 1.1Nov 6, 2024Group: Database references / Structure summary
Category: citation / citation_author ...citation / citation_author / pdbx_entry_details / pdbx_modification_feature
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _pdbx_entry_details.has_protein_modification

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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)38,3223
Polymers37,6361
Non-polymers6852
Water1267
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)145.572, 145.572, 145.572
Angle α, β, γ (deg.)90.000, 90.000, 90.000
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: 37636.441 Da / Num. of mol.: 1 / Fragment: kinase domain
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-R2E / 1-[4-[4-[[3,4-bis(chloranyl)-2-fluoranyl-phenyl]amino]-7-methoxy-quinazolin-6-yl]oxypiperidin-1-yl]propan-1-one / Poziotinib, bound form


Mass: 493.358 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H23Cl2FN4O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-CIT / CITRIC ACID


Mass: 192.124 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H8O7
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 7 / 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: 3.42 Å3/Da / Density % sol: 63.98 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 6.5 / Details: 0.1 M MES pH=6.5, 1.1 M Sodium Citrate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-C / Wavelength: 0.97918 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Jul 23, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
ReflectionResolution: 2.75→59.43 Å / Num. obs: 13469 / % possible obs: 99.7 % / Redundancy: 5 % / Biso Wilson estimate: 72.37 Å2 / Rpim(I) all: 0.069 / Rrim(I) all: 0.157 / Net I/σ(I): 8.3 / Num. measured all: 67815
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Mean I/σ(I) obsNum. measured allNum. unique obsRpim(I) allRrim(I) all% possible all
2.75-2.85.21.135186760.6381.464100
7.46-59.444.719.833447060.040.08797.1

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Processing

Software
NameVersionClassification
xia2data scaling
PHENIX1.20.1_4487refinement
PDB_EXTRACT3.27data extraction
xia2data reduction
PHASERphasing
Cootmodel building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2GS2

2gs2


Resolution: 2.75→59.43 Å / SU ML: 0.38 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 28.41 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2282 639 4.75 %
Rwork0.2049 12823 -
obs0.2061 13462 99.67 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 157.27 Å2 / Biso mean: 75.6135 Å2 / Biso min: 37.42 Å2
Refinement stepCycle: final / Resolution: 2.75→59.43 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2338 0 46 7 2391
Biso mean--81.21 61.43 -
Num. residues----293
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 5

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.75-2.960.37321210.308525212642100
2.96-3.260.32331320.261625692701100
3.26-3.730.27021220.231125582680100
3.74-4.690.20951200.179925642684100
4.7-59.430.18741440.17942611275599
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.2137-0.3206-0.26235.3491-2.43432.80980.07160.10440.466-0.21770.04410.5635-0.16140.0005-0.19330.6752-0.1596-0.08990.6713-0.01780.71587.2159-52.764531.9184
23.4924-1.2174-1.7841.66210.86454.79450.001-0.20490.64540.18090.1838-0.4989-0.44420.0968-0.22950.638-0.1741-0.0540.534-0.01190.67.1338-52.679730.5933
35.02222.10561.34894.54070.35013.7577-0.10980.12610.1355-0.1249-0.0348-0.0366-0.42770.19630.07930.4087-0.0325-0.01870.4127-0.05310.3466-4.8085-60.066522.9096
41.8320.40930.58776.69670.65790.78040.0343-1.14810.95551.2072-0.18460.9697-0.8828-1.11850.30480.9535-0.0486-0.08471.1896-0.23640.7217-13.1677-54.062838.1896
53.99080.01840.63872.6620.19912.9387-0.1721-0.44720.53990.0734-0.24520.3905-0.5782-0.44210.4020.44240.0105-0.07580.5479-0.14680.4663-23.0059-60.74523.2551
63.54660.61532.10191.28880.32882.5004-0.4024-0.07010.3419-0.05490.1113-0.1708-0.28470.49460.17570.6356-0.04210.06880.648-0.01820.51012.5151-65.396816.5847
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 696 through 725 )A696 - 725
2X-RAY DIFFRACTION2chain 'A' and (resid 726 through 768 )A726 - 768
3X-RAY DIFFRACTION3chain 'A' and (resid 769 through 853 )A769 - 853
4X-RAY DIFFRACTION4chain 'A' and (resid 854 through 876 )A854 - 876
5X-RAY DIFFRACTION5chain 'A' and (resid 877 through 977 )A877 - 977
6X-RAY DIFFRACTION6chain 'A' and (resid 978 through 1019 )A978 - 1019

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