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- PDB-6wxn: EGFR(T790M/V948R) in complex with LN3844 -

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Basic information

Entry
Database: PDB / ID: 6wxn
TitleEGFR(T790M/V948R) in complex with LN3844
ComponentsEpidermal growth factor receptor
KeywordsTRANSFERASE/TRANSFERASE inhibitor / Cancer / Inhibitor / TRANSFERASE / TRANSFERASE-TRANSFERASE inhibitor complex
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 / tongue development / response to UV-A / 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 / response to cobalamin / 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 / 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 / cellular response to epidermal growth factor stimulus / SHC1 events in ERBB2 signaling / cellular response to dexamethasone stimulus / ossification / positive regulation of synaptic transmission, glutamatergic / positive regulation of DNA repair / neuron projection morphogenesis / positive regulation of superoxide anion generation / positive regulation of epithelial cell proliferation / epithelial cell proliferation / liver regeneration / 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 / positive regulation of smooth muscle cell proliferation / cellular response to amino acid stimulus / cellular response to estradiol stimulus / lung development / EGFR downregulation / Signaling by ERBB2 TMD/JMD mutants / clathrin-coated endocytic vesicle membrane / synaptic membrane / placental growth factor receptor activity / insulin receptor activity / vascular endothelial growth factor receptor activity / 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 / boss receptor activity / protein tyrosine kinase collagen receptor activity / brain-derived neurotrophic factor receptor activity / stem cell factor receptor activity / GPI-linked ephrin receptor activity / transmembrane-ephrin receptor activity / epidermal growth factor receptor activity / fibroblast growth factor receptor activity / Constitutive Signaling by EGFRvIII / 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 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER / Chem-UEJ / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.76 Å
AuthorsHeppner, D.E. / Eck, M.J.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)R01CA201049 United States
CitationJournal: J.Med.Chem. / Year: 2022
Title: Design of a "Two-in-One" Mutant-Selective Epidermal Growth Factor Receptor Inhibitor That Spans the Orthosteric and Allosteric Sites.
Authors: Wittlinger, F. / Heppner, D.E. / To, C. / Gunther, M. / Shin, B.H. / Rana, J.K. / Schmoker, A.M. / Beyett, T.S. / Berger, L.M. / Berger, B.T. / Bauer, N. / Vasta, J.D. / Corona, C.R. / ...Authors: Wittlinger, F. / Heppner, D.E. / To, C. / Gunther, M. / Shin, B.H. / Rana, J.K. / Schmoker, A.M. / Beyett, T.S. / Berger, L.M. / Berger, B.T. / Bauer, N. / Vasta, J.D. / Corona, C.R. / Robers, M.B. / Knapp, S. / Janne, P.A. / Eck, M.J. / Laufer, S.A.
History
DepositionMay 11, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 19, 2021Provider: repository / Type: Initial release
Revision 1.1Dec 1, 2021Group: Database references / Category: citation / citation_author / database_2
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.2Feb 9, 2022Group: 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
Revision 1.3Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)151,7579
Polymers149,9174
Non-polymers1,8395
Water4,396244
1
D: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,1162
Polymers37,4791
Non-polymers6371
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
A: Epidermal growth factor receptor


Theoretical massNumber of molelcules
Total (without water)37,4791
Polymers37,4791
Non-polymers00
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
B: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,0103
Polymers37,4791
Non-polymers5312
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
C: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,1513
Polymers37,4791
Non-polymers6722
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)71.913, 102.742, 87.306
Angle α, β, γ (deg.)90.000, 101.200, 90.000
Int Tables number4
Space group name H-MP1211

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Components

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Protein , 1 types, 4 molecules DABC

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


Mass: 37479.367 Da / Num. of mol.: 4
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

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Non-polymers , 5 types, 249 molecules

#2: Chemical ChemComp-UEJ / N-(3-{5-[2-(acetylamino)pyridin-4-yl]-2-(methylsulfanyl)-1H-imidazol-4-yl}phenyl)-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-6-fluoro-3-hydroxybenzamide


Mass: 636.652 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C33H25FN6O5S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-ANP / PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER


Mass: 506.196 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H17N6O12P3 / Comment: AMP-PNP, energy-carrying molecule analogue*YM
#4: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#5: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 244 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY

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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: 2.11 Å3/Da / Density % sol: 41.72 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 5.5 / Details: 0.1 M BisTris, 25% PEG-3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-E / Wavelength: 0.97918 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Oct 21, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
ReflectionResolution: 1.76→85.7 Å / Num. obs: 119832 / % possible obs: 97.5 % / Redundancy: 3.5 % / CC1/2: 0.998 / Rmerge(I) obs: 0.061 / Rpim(I) all: 0.038 / Rrim(I) all: 0.072 / Net I/σ(I): 9 / Num. measured all: 414637 / Scaling rejects: 298
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
1.76-1.812.90.9022151473550.4820.6321.1091.181.7
7.87-85.73.60.024515814360.9990.0150.02827.8100

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Processing

Software
NameVersionClassification
PHENIX1.18_3845refinement
Aimless0.7.4data scaling
PDB_EXTRACT3.25data extraction
xia2data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6V5N

6v5n


Resolution: 1.76→65.78 Å / SU ML: 0.24 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 26.91 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2355 6019 5.03 %
Rwork0.208 113718 -
obs0.2093 119737 97.13 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 95.48 Å2 / Biso mean: 35.3366 Å2 / Biso min: 16.19 Å2
Refinement stepCycle: final / Resolution: 1.76→65.78 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9478 0 125 244 9847
Biso mean--32.88 35.67 -
Num. residues----1179
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 30

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.76-1.780.36321480.33182760290871
1.78-1.80.3651480.33363250339882
1.8-1.820.36681750.30673556373191
1.82-1.850.35051950.29373746394195
1.85-1.870.32161860.27913737392397
1.87-1.90.28531930.27033842403598
1.9-1.920.34571820.2683823400599
1.92-1.950.30062150.25093826404199
1.95-1.980.26622150.24743864407999
1.98-2.010.28132110.24513828403999
2.01-2.050.26842180.24063828404699
2.05-2.090.25392090.23343845405499
2.09-2.130.30921960.23123901409799
2.13-2.170.25612210.22373821404299
2.17-2.220.25022070.22043849405699
2.22-2.270.26492000.22093807400798
2.27-2.320.25612110.2243796400796
2.32-2.390.24182390.21343815405499
2.39-2.460.22071930.215538834076100
2.46-2.540.26781970.223839024099100
2.54-2.630.24312210.21538824103100
2.63-2.730.27252120.214338834095100
2.73-2.860.25531920.216239024094100
2.86-3.010.26312080.222238974105100
3.01-3.20.251950.21953894408999
3.2-3.440.22752050.20443831403698
3.44-3.790.21891930.189839414134100
3.79-4.340.19672130.167739134126100
4.34-5.460.17982230.167439254148100
5.47-65.780.18281980.1893971416999

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