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- PDB-6v6k: EGFR(T790M/V948R) in complex with LN2057 -

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Basic information

Entry
Database: PDB / ID: 6v6k
TitleEGFR(T790M/V948R) in complex with LN2057
ComponentsEpidermal growth factor receptor
KeywordsTRANSFERASE/TRANSFERASE inhibitor / egfr / inhibitor / TRANSFERASE-TRANSFERASE inhibitor complex
Function / homology
Function and homology information


response to hydroxyisoflavone / multivesicular body, internal vesicle lumen / positive regulation of prolactin secretion / negative regulation of cardiocyte differentiation / positive regulation of protein kinase C activity / diterpenoid metabolic process / Shc-EGFR complex / ovulation cycle / Inhibition of Signaling by Overexpressed EGFR / epidermal growth factor receptor activity ...response to hydroxyisoflavone / multivesicular body, internal vesicle lumen / positive regulation of prolactin secretion / negative regulation of cardiocyte differentiation / positive regulation of protein kinase C activity / diterpenoid metabolic process / Shc-EGFR complex / ovulation cycle / Inhibition of Signaling by Overexpressed EGFR / epidermal growth factor receptor activity / EGFR interacts with phospholipase C-gamma / positive regulation of mucus secretion / response to UV-A / epidermal growth factor binding / PLCG1 events in ERBB2 signaling / tongue development / midgut development / ERBB2-EGFR signaling pathway / hydrogen peroxide metabolic process / PTK6 promotes HIF1A stabilization / digestive tract morphogenesis / regulation of nitric-oxide synthase activity / morphogenesis of an epithelial fold / ERBB2 Activates PTK6 Signaling / intracellular vesicle / Signaling by EGFR / response to cobalamin / transmembrane receptor protein tyrosine kinase activator activity / protein tyrosine kinase activator activity / negative regulation of epidermal growth factor receptor signaling pathway / Signaling by ERBB4 / regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / eyelid development in camera-type eye / protein insertion into membrane / cerebral cortex cell migration / ERBB2 Regulates Cell Motility / regulation of JNK cascade / : / PI3K events in ERBB2 signaling / positive regulation of cyclin-dependent protein serine/threonine kinase activity / negative regulation of mitotic cell cycle / hair follicle development / MAP kinase kinase kinase activity / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / embryonic placenta development / positive regulation of bone resorption / positive regulation of G1/S transition of mitotic cell cycle / GAB1 signalosome / positive regulation of nitric oxide mediated signal transduction / salivary gland morphogenesis / peptidyl-tyrosine autophosphorylation / regulation of peptidyl-tyrosine phosphorylation / positive regulation of phosphorylation / positive regulation of glial cell proliferation / positive regulation of vasoconstriction / Signaling by ERBB2 / cellular response to epidermal growth factor stimulus / cellular response to cadmium ion / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / positive regulation of DNA repair / EGFR Transactivation by Gastrin / GRB2 events in ERBB2 signaling / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / transmembrane receptor protein tyrosine kinase activity / SHC1 events in ERBB2 signaling / ossification / positive regulation of synaptic transmission, glutamatergic / neurogenesis / cellular response to dexamethasone stimulus / basal plasma membrane / regulation of ERK1 and ERK2 cascade / neuron projection morphogenesis / positive regulation of superoxide anion generation / positive regulation of DNA replication / Signal transduction by L1 / epithelial cell proliferation / cellular response to estradiol stimulus / NOTCH3 Activation and Transmission of Signal to the Nucleus / positive regulation of epithelial cell proliferation / astrocyte activation / liver regeneration / positive regulation of protein localization to plasma membrane / EGFR downregulation / cell surface receptor protein tyrosine kinase signaling pathway / cellular response to amino acid stimulus / positive regulation of smooth muscle cell proliferation / Signaling by ERBB2 TMD/JMD mutants / positive regulation of MAP kinase activity / clathrin-coated endocytic vesicle membrane / lung development / Constitutive Signaling by EGFRvIII / Signaling by ERBB2 ECD mutants / epidermal growth factor receptor signaling pathway / Signaling by ERBB2 KD Mutants / negative regulation of protein catabolic process / receptor protein-tyrosine kinase / Downregulation of ERBB2 signaling / kinase binding / ruffle membrane
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 / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; 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
Chem-QQJ / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.2 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: 2020
Title: Structural Basis for EGFR Mutant Inhibition by Trisubstituted Imidazole Inhibitors.
Authors: Heppner, D.E. / Gunther, M. / Wittlinger, F. / Laufer, S.A. / Eck, M.J.
History
DepositionDec 5, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 22, 2020Provider: repository / Type: Initial release
Revision 1.1May 6, 2020Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Oct 11, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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
E: Epidermal growth factor receptor
F: Epidermal growth factor receptor
G: Epidermal growth factor receptor
H: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)303,24224
Polymers299,1388
Non-polymers4,10416
Water12,809711
1
D: Epidermal growth factor receptor
hetero molecules

B: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)75,8116
Polymers74,7852
Non-polymers1,0264
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_545-x,y-1/2,-z1
Buried area3240 Å2
ΔGint-32 kcal/mol
Surface area26790 Å2
MethodPISA
2
A: Epidermal growth factor receptor
H: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)75,8116
Polymers74,7852
Non-polymers1,0264
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3420 Å2
ΔGint-44 kcal/mol
Surface area26590 Å2
MethodPISA
3
C: Epidermal growth factor receptor
hetero molecules

G: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)75,8116
Polymers74,7852
Non-polymers1,0264
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_655-x+1,y+1/2,-z1
Buried area3410 Å2
ΔGint-44 kcal/mol
Surface area26630 Å2
MethodPISA
4
E: Epidermal growth factor receptor
F: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)75,8116
Polymers74,7852
Non-polymers1,0264
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3440 Å2
ΔGint-45 kcal/mol
Surface area26690 Å2
MethodPISA
Unit cell
Length a, b, c (Å)71.599, 102.455, 174.043
Angle α, β, γ (deg.)90.000, 101.250, 90.000
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11(chain A and (resid 701 through 862 or resid 877 through 921 or resid 923 through 1301))
21(chain B and (resid 701 through 921 or resid 923 through 984 or resid 987 through 1301))
31(chain C and (resid 701 through 862 or resid 877...
41(chain D and (resid 701 through 862 or resid 877...
51(chain E and (resid 701 through 862 or resid 877...
61(chain F and (resid 701 through 862 or resid 877...
71(chain G and (resid 701 through 862 or resid 877...
81(chain H and (resid 701 through 862 or resid 877...

NCS domain segments:
Dom-IDComponent-IDEns-IDSelection detailsAuth asym-IDAuth seq-ID
111(chain A and (resid 701 through 862 or resid 877 through 921 or resid 923 through 1301))A701 - 862
121(chain A and (resid 701 through 862 or resid 877 through 921 or resid 923 through 1301))A877 - 921
131(chain A and (resid 701 through 862 or resid 877 through 921 or resid 923 through 1301))A923 - 1301
211(chain B and (resid 701 through 921 or resid 923 through 984 or resid 987 through 1301))B701 - 921
221(chain B and (resid 701 through 921 or resid 923 through 984 or resid 987 through 1301))B923 - 984
231(chain B and (resid 701 through 921 or resid 923 through 984 or resid 987 through 1301))B987 - 1301
311(chain C and (resid 701 through 862 or resid 877...C701 - 862
321(chain C and (resid 701 through 862 or resid 877...C877 - 921
331(chain C and (resid 701 through 862 or resid 877...C923 - 984
341(chain C and (resid 701 through 862 or resid 877...C987 - 1301
411(chain D and (resid 701 through 862 or resid 877...D701 - 862
421(chain D and (resid 701 through 862 or resid 877...D877 - 921
431(chain D and (resid 701 through 862 or resid 877...D923 - 984
441(chain D and (resid 701 through 862 or resid 877...D987 - 1201
451(chain D and (resid 701 through 862 or resid 877...D1401
511(chain E and (resid 701 through 862 or resid 877...E701 - 862
521(chain E and (resid 701 through 862 or resid 877...E877 - 921
531(chain E and (resid 701 through 862 or resid 877...E923 - 984
541(chain E and (resid 701 through 862 or resid 877...E987 - 1301
611(chain F and (resid 701 through 862 or resid 877...F701 - 862
621(chain F and (resid 701 through 862 or resid 877...F877 - 921
631(chain F and (resid 701 through 862 or resid 877...F923 - 984
641(chain F and (resid 701 through 862 or resid 877...F987 - 1301
711(chain G and (resid 701 through 862 or resid 877...G701 - 862
721(chain G and (resid 701 through 862 or resid 877...G877 - 921
731(chain G and (resid 701 through 862 or resid 877...G923 - 984
741(chain G and (resid 701 through 862 or resid 877...G987 - 1301
811(chain H and (resid 701 through 862 or resid 877...H701 - 862
821(chain H and (resid 701 through 862 or resid 877...H877 - 921
831(chain H and (resid 701 through 862 or resid 877...H923 - 984
841(chain H and (resid 701 through 862 or resid 877...H987 - 1301

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Components

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


Mass: 37392.285 Da / Num. of mol.: 8
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EGFR, ERBB, ERBB1, HER1 / Plasmid: pEX / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P00533, receptor protein-tyrosine kinase
#2: Chemical
ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: Cl
#3: Chemical
ChemComp-QQJ / N-[3-({4-[4-(4-fluorophenyl)-2-(methylsulfanyl)-1H-imidazol-5-yl]pyridin-2-yl}amino)-4-methoxyphenyl]propanamide


Mass: 477.554 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C25H24FN5O2S / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 711 / Source method: isolated from a natural source / Formula: H2O
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: 2.09 Å3/Da / Density % sol: 41.1 % / Mosaicity: 0 °
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 5.5 / Details: 0.1 M Bis-Tris, 25% PEG3350

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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: Jun 11, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
ReflectionResolution: 2.2→85.36 Å / Num. obs: 117626 / % possible obs: 94.1 % / Redundancy: 3.1 % / CC1/2: 0.998 / Rmerge(I) obs: 0.081 / Rpim(I) all: 0.052 / Rrim(I) all: 0.097 / Net I/σ(I): 7.8 / Num. measured all: 369134 / Scaling rejects: 205
Reflection shell

Diffraction-ID: 1 / Redundancy: 3.1 %

Resolution (Å)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
2.2-2.260.5522700688400.820.3630.663295.9
9.84-85.360.027412613220.9990.0170.03216.689.4

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Processing

Software
NameVersionClassification
PHENIX1.17.1_3660refinement
Aimless0.7.4data scaling
PDB_EXTRACT3.25data extraction
xia2data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5d41

5d41


Resolution: 2.2→85.35 Å / SU ML: 0.26 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 26.93 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2394 5816 4.96 %
Rwork0.2139 111439 -
obs0.2152 117255 93.65 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 108.76 Å2 / Biso mean: 36.539 Å2 / Biso min: 11.71 Å2
Refinement stepCycle: final / Resolution: 2.2→85.35 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms19714 0 280 711 20705
Biso mean--29.34 38.02 -
Num. residues----2454
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDRmsType
11A10290X-RAY DIFFRACTION17.348TORSIONAL
12B10290X-RAY DIFFRACTION17.348TORSIONAL
13C10290X-RAY DIFFRACTION17.348TORSIONAL
14D10290X-RAY DIFFRACTION17.348TORSIONAL
15E10290X-RAY DIFFRACTION17.348TORSIONAL
16F10290X-RAY DIFFRACTION17.348TORSIONAL
17G10290X-RAY DIFFRACTION17.348TORSIONAL
18H10290X-RAY DIFFRACTION17.348TORSIONAL
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 (%)
2.2-2.220.35371620.27733802396495
2.22-2.250.29531870.26653745393295
2.25-2.280.3061800.26373811399196
2.28-2.310.31981760.2613796397296
2.31-2.340.29121950.25843726392195
2.34-2.370.30881920.24753768396095
2.37-2.40.29132240.24793729395395
2.4-2.440.27871730.24613695386893
2.44-2.480.30511880.26563570375891
2.48-2.520.29391740.25283348352285
2.52-2.560.30881550.25693875403095
2.56-2.610.26281950.24913785398097
2.61-2.660.30121750.23863846402196
2.66-2.710.28392240.23653743396796
2.71-2.770.25662180.23473826404496
2.77-2.840.27232270.23893688391595
2.84-2.910.26921860.23423736392294
2.91-2.990.2642180.23273665388393
2.99-3.070.23872080.23683334354286
3.07-3.170.25671830.22913724390794
3.17-3.290.25312180.22043855407397
3.29-3.420.24161820.21593853403596
3.42-3.570.24421960.20483789398596
3.57-3.760.19981990.19313746394594
3.76-40.18242060.18393477368388
4-4.310.17722090.16843664387392
4.31-4.740.18492080.1673814402296
4.74-5.420.2232020.18363748395094
5.42-6.830.23021590.2053579373889
6.83-85.350.20711970.19093702389990

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