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- PDB-8to3: EGFR(T790M/V948R) in complex with LN5461 -

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Basic information

Entry
Database: PDB / ID: 8to3
TitleEGFR(T790M/V948R) in complex with LN5461
ComponentsEpidermal growth factor receptor
KeywordsTRANSFERASE / Cancer / Inhibitor / Kinase
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
PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER / : / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.49 Å
AuthorsChitnis, S.P. / Pham, C.D. / Heppner, D.E.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Center for Advancing Translational Sciences (NIH/NCATS)UL1TR001412 United States
CitationJournal: J.Med.Chem. / Year: 2024
Title: Tilting the Scales toward EGFR Mutant Selectivity: Expanding the Scope of Bivalent "Type V" Kinase Inhibitors.
Authors: Wittlinger, F. / Chitnis, S.P. / Pham, C.D. / Damghani, T. / Patel, K.B. / Mollers, M. / Schaeffner, I.K. / Abidakun, O.A. / Deng, M.Q. / Ogboo, B.C. / Rasch, A. / Beyett, T.S. / Buckley, B. ...Authors: Wittlinger, F. / Chitnis, S.P. / Pham, C.D. / Damghani, T. / Patel, K.B. / Mollers, M. / Schaeffner, I.K. / Abidakun, O.A. / Deng, M.Q. / Ogboo, B.C. / Rasch, A. / Beyett, T.S. / Buckley, B. / Feru, F. / Shaurova, T. / Knappe, C. / Eck, M.J. / Hershberger, P.A. / Scott, D.A. / Brandt, A.L. / Laufer, S.A. / Heppner, D.E.
History
DepositionAug 2, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 28, 2024Provider: repository / Type: Initial release
Revision 1.1Mar 12, 2025Group: Database references / Structure summary
Category: audit_author / citation ...audit_author / citation / citation_author / pdbx_entry_details
Item: _audit_author.name / _citation.country ..._audit_author.name / _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
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)152,23211
Polymers149,9174
Non-polymers2,3147
Water1,802100
1
D: 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
2
A: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,2022
Polymers37,4791
Non-polymers7231
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)38,0103
Polymers37,4791
Non-polymers5312
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)56.999, 73.369, 150.591
Angle α, β, γ (deg.)90.00, 99.60, 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: 37479.367 Da / Num. of mol.: 4 / Mutation: T790M, V948R
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-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Mg
#3: Chemical ChemComp-ANP / PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER


Mass: 506.196 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C10H17N6O12P3 / Comment: AMP-PNP, energy-carrying molecule analogue*YM
#4: Chemical ChemComp-IXC / 3-hydroxy-N-{(3P)-3-[(4P)-2-(methylsulfanyl)-5-{2-[4-(piperazin-1-yl)anilino]pyridin-4-yl}-1H-imidazol-4-yl]phenyl}-2-[(1-oxo-1,3-dihydro-2H-isoindol-2-yl)methyl]benzamide


Mass: 722.857 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C41H38N8O3S / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 100 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationN

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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: 2.07 Å3/Da / Density % sol: 40.61 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 5.5 / Details: Bis-Tris (100mM), 25% PEG-3350 and TCEP (5mM)

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: NSLS-II / Beamline: 17-ID-2 / Wavelength: 0.97927 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Jul 21, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97927 Å / Relative weight: 1
ReflectionResolution: 2.49→56.2 Å / Num. obs: 42889 / % possible obs: 100 % / Redundancy: 6.7 % / Biso Wilson estimate: 43.36 Å2 / CC1/2: 0.986 / Rmerge(I) obs: 0.191 / Rpim(I) all: 0.08 / Rrim(I) all: 0.207 / Net I/σ(I): 6.3
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
2.5-2.596.41.3482840844730.6690.5841.4721.499.9
9.35-55.836.70.0458228670.9910.0170.04413.899.5

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Processing

Software
NameVersionClassification
PHENIX1.19_4092refinement
Aimless0.7.7data scaling
PDB_EXTRACT3.27data extraction
DIALSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6WXN

6wxn


Resolution: 2.49→56.2 Å / SU ML: 0.34 / Cross valid method: THROUGHOUT / σ(F): 1.36 / Phase error: 28.86 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2687 1979 4.61 %
Rwork0.2292 --
obs0.231 42889 98.84 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.49→56.2 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9382 0 149 100 9631
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.019759
X-RAY DIFFRACTIONf_angle_d1.22513223
X-RAY DIFFRACTIONf_dihedral_angle_d19.3693707
X-RAY DIFFRACTIONf_chiral_restr0.0621479
X-RAY DIFFRACTIONf_plane_restr0.011638
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.49-2.550.37381180.33332537X-RAY DIFFRACTION87
2.55-2.620.34471470.31362937X-RAY DIFFRACTION99
2.62-2.690.37021400.30562916X-RAY DIFFRACTION100
2.69-2.780.35541370.2992912X-RAY DIFFRACTION100
2.78-2.880.30371430.27712968X-RAY DIFFRACTION100
2.88-30.26971430.26042958X-RAY DIFFRACTION100
3-3.130.26391420.25372905X-RAY DIFFRACTION100
3.13-3.30.31511500.25282956X-RAY DIFFRACTION100
3.3-3.50.25181420.24092933X-RAY DIFFRACTION100
3.5-3.770.27091420.21082952X-RAY DIFFRACTION100
3.77-4.150.24781440.20192954X-RAY DIFFRACTION100
4.15-4.750.2531460.18652976X-RAY DIFFRACTION100
4.76-5.990.23931430.20282977X-RAY DIFFRACTION100
5.99-56.20.20631420.19883029X-RAY DIFFRACTION99

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