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- PDB-7zyp: Crystal Structure of EGFR-T790M/C797S in Complex with Reversible ... -

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Basic information

Entry
Database: PDB / ID: 7zyp
TitleCrystal Structure of EGFR-T790M/C797S in Complex with Reversible Aminopyrimidine 9
ComponentsEpidermal growth factor receptor
KeywordsTRANSFERASE / EGFR / T790M/C797S / inhibitor
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 / 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
Chem-R25 / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.8 Å
AuthorsNiggenaber, J. / Kleinboelting, S. / Mueller, M.P. / Rauh, D.
Funding support Germany, European Union, 3items
OrganizationGrant numberCountry
German Federal Ministry for Education and ResearchBMBF 01GS08104 Germany
German Federal Ministry for Education and ResearchBMBF 01ZX1303C Germany
European Regional Development FundEFRE-800400European Union
CitationJournal: Acs Med.Chem.Lett. / Year: 2023
Title: Addressing the Osimertinib Resistance Mutation EGFR-L858R/C797S with Reversible Aminopyrimidines.
Authors: Grabe, T. / Jeyakumar, K. / Niggenaber, J. / Schulz, T. / Koska, S. / Kleinbolting, S. / Beck, M.E. / Muller, M.P. / Rauh, D.
History
DepositionMay 25, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 3, 2023Provider: repository / Type: Initial release
Revision 1.1May 24, 2023Group: Structure summary / Category: audit_author
Revision 1.2May 31, 2023Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.3Feb 7, 2024Group: 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

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Assembly

Deposited unit
A: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,4253
Polymers37,7161
Non-polymers7102
Water362
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area290 Å2
ΔGint3 kcal/mol
Surface area15290 Å2
MethodPISA
Unit cell
Length a, b, c (Å)141.800, 141.800, 141.800
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number197
Space group name H-MI23
Space group name HallI223

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Components

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


Mass: 37715.613 Da / Num. of mol.: 1
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-R25 / propan-2-yl 2-[[4-(4-azanylpiperidin-1-yl)-2-methoxy-phenyl]amino]-4-(1-methylindol-3-yl)pyrimidine-5-carboxylate


Mass: 514.619 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H34N6O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-MES / 2-(N-MORPHOLINO)-ETHANESULFONIC ACID


Mass: 195.237 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H13NO4S / Comment: pH buffer*YM
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 2 / 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: 3.15 Å3/Da / Density % sol: 60.95 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 1.5 K-Na-tartrate, 100 mM Na-MES (pH 7.5), 5.5 mg/mL EGFR-WT (in 100 mM NaCl, 25 mM Tris-HCl, 10 % glycerol, 1 mM TCEP) pH 8.0) 1 ul reservoir + 1 ul solution

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.9998 Å
DetectorType: DECTRIS EIGER2 X 16M / Detector: PIXEL / Date: Feb 5, 2020
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9998 Å / Relative weight: 1
ReflectionResolution: 2.8→44.84 Å / Num. obs: 11850 / % possible obs: 100 % / Redundancy: 38.28 % / Biso Wilson estimate: 92.2 Å2 / CC1/2: 1 / Rrim(I) all: 0.139 / Net I/σ(I): 21.67
Reflection shellResolution: 2.8→2.9 Å / Redundancy: 42.91 % / Mean I/σ(I) obs: 2.11 / Num. unique obs: 1162 / CC1/2: 0.681 / Rrim(I) all: 2.831 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
PHENIX1.20.1_4487refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6S89

6s89


Resolution: 2.8→44.84 Å / SU ML: 0.3708 / Cross valid method: FREE R-VALUE / σ(F): 1.37 / Phase error: 27.495
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2281 593 5.01 %
Rwork0.1987 11255 -
obs0.2002 11848 99.98 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 87.25 Å2
Refinement stepCycle: LAST / Resolution: 2.8→44.84 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2268 0 50 2 2320
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00332373
X-RAY DIFFRACTIONf_angle_d0.60113240
X-RAY DIFFRACTIONf_chiral_restr0.0449370
X-RAY DIFFRACTIONf_plane_restr0.0039405
X-RAY DIFFRACTIONf_dihedral_angle_d15.1913833
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.8-3.080.31291470.28062782X-RAY DIFFRACTION100
3.08-3.530.27331460.242782X-RAY DIFFRACTION100
3.53-4.440.22161470.19382799X-RAY DIFFRACTION100
4.44-44.840.2091530.18122892X-RAY DIFFRACTION99.93
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)
13.837852482881.67004350045-3.008175817484.55201301797-4.309443583828.679205345780.370302743492-0.2997290671070.1575930691320.1510825325250.005104996752140.460234589199-0.149936292448-0.486156044266-0.3161607004750.605263226016-0.147782176816-0.01226927957130.766210644734-0.08881359275310.718366285937335.167923436275.767548103113.477090945
21.64813988672-0.810648902305-0.09024635599888.3125677445-3.197339756815.80225175022-0.3295321597020.846161335766-0.3493216349670.4207964641360.03740704499320.5954235677090.311390612067-0.265936858418-0.3744586275940.696343612367-0.255096661334-0.01512979799851.03336998456-0.07798797797340.649734575741333.570096067271.529351814116.152808527
31.828659882433.024212648991.393246068786.823558577450.1313986423654.1444469447-0.2400100268540.0488559891334-0.0781929175374-0.4746512431650.272125787540.282941976167-0.350034478554-0.4370256296210.09881693127260.758836695182-0.00857792220887-0.0001862090303090.859705162241-0.1118304558670.869002746085336.468148719280.74993567109.293846396
43.600454440612.969133142432.084223275838.678955703773.251934901762.823056696850.130204094657-0.2265503219030.1467655554450.736413454422-0.4429981839270.1668276439720.237275483423-0.6199730686890.1759949589830.6343030503110.0415867360824-0.06476524584420.649445058995-0.003850730454680.55684464245342.782928899290.378346269125.013043906
54.227852363793.55347346992-1.391043374563.826291436080.5388582994254.294408111-0.1676418537090.315382359993-0.20328506566-0.255909549630.163152898490.482214658430.0141797779316-0.4193716551270.2425948207460.573912313476-0.013744238442-0.04954684933450.589716761252-0.03910612710570.516260405447341.306834504290.680937408118.398299881
65.756823047651.9245368055-0.2717500529093.73175836786-1.412275353049.64205055692-0.1440023823661.103567732781.23585278438-0.7410074697150.2249644009960.332155504269-0.9221451307210.1895480543870.3122798882151.21798657101-0.016563414806-0.02454512877111.10254724884-0.139055024321.19954390843338.475272925295.261894628104.060142839
73.09142742645-0.675602783684-0.6237904315817.469667677211.370898235947.37902833171-0.0835085398154-0.0805690180756-0.284701704817-1.10318111965-0.1327437115950.861999145640.0434098902842-0.6477174881880.3044860747311.057488688230.112423830599-0.3046831685360.841705213986-0.1240540666570.921785621349334.0285729305.129822796109.412954467
82.72652137275-1.895082742531.944514897766.308446780393.664067264166.84406077353-0.183474552759-0.4392591651550.0506190666467-0.458378062105-0.2820722061650.55856117964-0.697832228337-0.8015565237650.4861187830030.571529996670.0545321109768-0.09703675653910.612160385829-0.07516522451960.521696066116340.65353615308.196781687121.057482058
97.28439416096-1.53126206623-3.307519261265.507791871515.049508215978.039316960770.0487212760198-0.9463146849030.129191467776-0.01339932659710.505616202798-0.4488291442790.8027884994191.37594279188-0.0276549361840.783151347827-0.0121965425002-0.09145365546880.692427437523-0.03877026849680.641507407689354.208554235301.504181647127.9610648
104.15644534350.793367758372.702111246538.477874108044.281680383744.64621065510.5658037564540.292540605808-0.9093711236370.309758789301-0.4191374190840.243006051065-0.4511070340430.3732637132160.01553651014410.770940064524-0.0959434084463-0.04631744295550.930821467690.1183278272990.904458870801346.451054013274.265144463124.361916984
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 695 through 731 )695 - 7311 - 37
22chain 'A' and (resid 732 through 752 )732 - 75238 - 58
33chain 'A' and (resid 753 through 786 )753 - 78659 - 92
44chain 'A' and (resid 787 through 830 )787 - 83093 - 136
55chain 'A' and (resid 831 through 853 )831 - 853137 - 159
66chain 'A' and (resid 854 through 873 )854 - 873160 - 179
77chain 'A' and (resid 874 through 892 )874 - 892180 - 198
88chain 'A' and (resid 893 through 960 )893 - 960199 - 266
99chain 'A' and (resid 961 through 982 )961 - 982267 - 288
1010chain 'A' and (resid 983 through 1019 )983 - 1019289 - 305

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