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- PDB-8wd4: EGFR(L858R/T790/C797S) in complex with compound 5j -

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Basic information

Entry
Database: PDB / ID: 8wd4
TitleEGFR(L858R/T790/C797S) in complex with compound 5j
ComponentsEpidermal growth factor receptor
KeywordsONCOPROTEIN / EGFR / C797S / Drug Discovery
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 / 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 / eyelid development in camera-type eye / regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / protein insertion into membrane / cerebral cortex cell migration / ERBB2 Regulates Cell Motility / Respiratory syncytial virus (RSV) attachment and entry / 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 / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / MAP kinase kinase kinase activity / embryonic placenta development / positive regulation of bone resorption / positive regulation of G1/S transition of mitotic cell cycle / GAB1 signalosome / 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 / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / cellular response to cadmium ion / EGFR Transactivation by Gastrin / positive regulation of DNA repair / 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 / positive regulation of synaptic transmission, glutamatergic / cellular response to dexamethasone stimulus / ossification / neurogenesis / regulation of ERK1 and ERK2 cascade / basal plasma membrane / neuron projection morphogenesis / positive regulation of superoxide anion generation / positive regulation of DNA replication / epithelial cell proliferation / Signal transduction by L1 / cellular response to estradiol stimulus / positive regulation of epithelial cell proliferation / NOTCH3 Activation and Transmission of Signal to the Nucleus / astrocyte activation / liver regeneration / positive regulation of protein localization to plasma membrane / EGFR downregulation / 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 / lung development / clathrin-coated endocytic vesicle membrane / Constitutive Signaling by EGFRvIII / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / epidermal growth factor receptor signaling pathway / negative regulation of protein catabolic process / receptor protein-tyrosine kinase / Downregulation of ERBB2 signaling / kinase binding / ruffle membrane / positive regulation of miRNA transcription / cell-cell adhesion
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 / 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
Chem-W7W / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.55 Å
AuthorsNishikawa, Y.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2023
Title: Synthesis, activity, and their relationships of 2,4-diaminonicotinamide derivatives as EGFR inhibitors targeting C797S mutation.
Authors: Kageji, H. / Momose, T. / Nagamoto, Y. / Togashi, N. / Yasumatsu, I. / Nishikawa, Y. / Kihara, K. / Hiramoto, K. / Minami, M. / Kasanuki, N. / Isoyama, T. / Naito, H.
History
DepositionSep 14, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Dec 20, 2023Provider: repository / Type: Initial release
Revision 1.1Jan 3, 2024Group: Database references / Category: citation / Item: _citation.journal_volume

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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)37,9763
Polymers37,4061
Non-polymers5702
Water66737
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)145.327, 145.327, 145.327
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number197
Space group name H-MI23
Space group name HallI223
Symmetry operation#1: x,y,z
#2: z,x,y
#3: y,z,x
#4: -y,-z,x
#5: z,-x,-y
#6: -y,z,-x
#7: -z,-x,y
#8: -z,x,-y
#9: y,-z,-x
#10: x,-y,-z
#11: -x,y,-z
#12: -x,-y,z
#13: x+1/2,y+1/2,z+1/2
#14: z+1/2,x+1/2,y+1/2
#15: y+1/2,z+1/2,x+1/2
#16: -y+1/2,-z+1/2,x+1/2
#17: z+1/2,-x+1/2,-y+1/2
#18: -y+1/2,z+1/2,-x+1/2
#19: -z+1/2,-x+1/2,y+1/2
#20: -z+1/2,x+1/2,-y+1/2
#21: y+1/2,-z+1/2,-x+1/2
#22: x+1/2,-y+1/2,-z+1/2
#23: -x+1/2,y+1/2,-z+1/2
#24: -x+1/2,-y+1/2,z+1/2

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Components

#1: Protein Epidermal growth factor receptor


Mass: 37406.297 Da / Num. of mol.: 1 / Mutation: L858R,T790M,C797S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EGFR / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P00533
#2: Chemical ChemComp-W7W / ~{N}-[3,3-bis(fluoranyl)propyl]-4-[[(2~{S})-butan-2-yl]amino]-6-[[2-(1-cyclopropylsulfonylpyrazol-4-yl)pyrimidin-4-yl]amino]pyridine-3-carboxamide


Mass: 534.582 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H28F2N8O3S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-CL / CHLORIDE ION


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


Mass: 18.015 Da / Num. of mol.: 37 / 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: 3.42 Å3/Da / Density % sol: 64.02 %
Crystal growTemperature: 297 K / Method: vapor diffusion / Details: 0.46 M Trisodium citrate, pH 7.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Nov 1, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.55→45.96 Å / Num. obs: 16233 / % possible obs: 96.5 % / Redundancy: 3 % / Biso Wilson estimate: 63.01 Å2 / CC1/2: 0.998 / Rrim(I) all: 0.061 / Net I/σ(I): 17.62
Reflection shellResolution: 2.55→2.7 Å / Mean I/σ(I) obs: 1.6 / Num. unique obs: 2624 / CC1/2: 0.535 / Rrim(I) all: 0.885 / % possible all: 97.3

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Processing

Software
NameVersionClassification
XDSdata reduction
XDSdata scaling
PHENIXphasing
PHENIX1.19.2_4158refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.55→45.96 Å / SU ML: 0.4699 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 28.0257
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2297 926 5.71 %
Rwork0.1987 15301 -
obs0.2005 16227 96.53 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 69.14 Å2
Refinement stepCycle: LAST / Resolution: 2.55→45.96 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2396 0 38 37 2471
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01212486
X-RAY DIFFRACTIONf_angle_d1.52163363
X-RAY DIFFRACTIONf_chiral_restr0.0899376
X-RAY DIFFRACTIONf_plane_restr0.0072419
X-RAY DIFFRACTIONf_dihedral_angle_d13.8809947
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.55-2.680.34731130.30632241X-RAY DIFFRACTION98.12
2.69-2.850.41171460.34532166X-RAY DIFFRACTION96.98
2.85-3.070.31631430.2452158X-RAY DIFFRACTION97.87
3.07-3.380.2991200.23312203X-RAY DIFFRACTION96.99
3.38-3.870.20471010.1832181X-RAY DIFFRACTION95.64
3.87-4.880.18391720.1562140X-RAY DIFFRACTION95.93
4.88-45.960.20021310.18022212X-RAY DIFFRACTION94.29
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)
10.6612726851680.165199852712-0.3326086467851.353165696250.30880964440.2412551706440.0652779367570.249006921149-0.07641254910570.134802057476-0.1270474631080.4896043404370.0827777614918-0.203620910262-1.12945702576E-70.589858241407-0.01485832982730.07918493750960.6657644431720.02053819805640.70767565132753.3371018446-31.21294041726.92124273304
20.57893843014-0.380293108968-0.2256273713291.95467210888-0.09271578049180.27724128828-0.103422309898-0.223152144934-0.297820315936-0.1622311477640.04197359679870.5780431234590.1078195293380.0488079083007-3.77338275057E-80.542704465663-0.07024638130780.09834698356880.5797152792570.0388372022890.60641874023653.7203370091-31.75021135715.44516968561
32.004395952680.523576124326-0.829918226111.94577144403-1.417381879193.92965576166-0.2021811177940.1896474676090.0729727574686-0.1181071194160.3901223881590.3202613912030.410111086965-0.5979115407360.01162336065190.436653096726-0.08342450548750.004171069316910.4577906531320.06573767610120.45852731915458.9313789458-23.2743747221-16.811978347
40.863522878120.7512728889770.232350093310.73565490533-0.1324680682971.127154700940.0518919630421-0.1887335668280.4315066164930.09638916282510.1749438203560.165476732799-0.501559244470.224778980508-3.52755584054E-80.6305341154710.07128162152080.06931023106890.508629560335-0.02056756466340.58702967610468.0335425563-14.7008934147-5.31032771743
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION / Auth asym-ID: A / Label asym-ID: A

IDRefine TLS-IDSelection detailsAuth seq-IDLabel seq-ID
11chain 'A' and (resid 694 through 731 )694 - 7311 - 38
22chain 'A' and (resid 732 through 791 )732 - 79139 - 95
33chain 'A' and (resid 792 through 960 )792 - 96096 - 253
44chain 'A' and (resid 961 through 1019 )961 - 1019254 - 299

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