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- PDB-7zyn: Crystal Structure of EGFR-T790M/C797S in Complex with WZ4002 -

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Basic information

Entry
Database: PDB / ID: 7zyn
TitleCrystal Structure of EGFR-T790M/C797S in Complex with WZ4002
ComponentsEpidermal growth factor receptor
KeywordsTRANSFERASE / EGFR / T790M/C797S / inhibitor
Function / homology
Function and homology information


multivesicular body, internal vesicle lumen / negative regulation of cardiocyte differentiation / Shc-EGFR complex / positive regulation of protein kinase C signaling / Inhibition of Signaling by Overexpressed EGFR / EGFR interacts with phospholipase C-gamma / epidermal growth factor receptor activity / regulation of peptidyl-tyrosine phosphorylation / epidermal growth factor binding / response to UV-A ...multivesicular body, internal vesicle lumen / negative regulation of cardiocyte differentiation / Shc-EGFR complex / positive regulation of protein kinase C signaling / Inhibition of Signaling by Overexpressed EGFR / EGFR interacts with phospholipase C-gamma / epidermal growth factor receptor activity / regulation of peptidyl-tyrosine phosphorylation / epidermal growth factor binding / response to UV-A / PLCG1 events in ERBB2 signaling / ERBB2-EGFR signaling pathway / morphogenesis of an epithelial fold / PTK6 promotes HIF1A stabilization / ERBB2 Activates PTK6 Signaling / digestive tract morphogenesis / Signaling by EGFR / 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 / positive regulation of phosphorylation / positive regulation of peptidyl-serine phosphorylation / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / hair follicle development / MAP kinase kinase kinase activity / GAB1 signalosome / positive regulation of G1/S transition of mitotic cell cycle / embryonic placenta development / salivary gland morphogenesis / Signaling by ERBB2 / GRB2 events in EGFR signaling / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / SHC1 events in EGFR signaling / transmembrane receptor protein tyrosine kinase activity / EGFR Transactivation by Gastrin / GRB2 events in ERBB2 signaling / SHC1 events in ERBB2 signaling / ossification / NOTCH3 Activation and Transmission of Signal to the Nucleus / positive regulation of DNA repair / basal plasma membrane / cellular response to epidermal growth factor stimulus / EGFR downregulation / positive regulation of DNA replication / epithelial cell proliferation / Signal transduction by L1 / positive regulation of epithelial cell proliferation / positive regulation of protein localization to plasma membrane / cellular response to amino acid stimulus / phosphatidylinositol 3-kinase/protein kinase B signal transduction / cellular response to estradiol stimulus / clathrin-coated endocytic vesicle membrane / Signaling by ERBB2 TMD/JMD mutants / Constitutive Signaling by EGFRvIII / Downregulation of ERBB2 signaling / cell-cell adhesion / receptor protein-tyrosine kinase / negative regulation of protein catabolic process / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / positive regulation of miRNA transcription / kinase binding / ruffle membrane / positive regulation of protein phosphorylation / epidermal growth factor receptor signaling pathway / neuron differentiation / cell morphogenesis / positive regulation of fibroblast proliferation / HCMV Early Events / Constitutive Signaling by Aberrant PI3K in Cancer / actin filament binding / Cargo recognition for clathrin-mediated endocytosis / cell junction / transmembrane signaling receptor activity / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / positive regulation of canonical Wnt signaling pathway / Clathrin-mediated endocytosis / PIP3 activates AKT signaling / virus receptor activity / ATPase binding / RAF/MAP kinase cascade / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / positive regulation of cell growth / double-stranded DNA binding / protein tyrosine kinase activity / early endosome membrane / protein phosphatase binding / nuclear membrane / basolateral plasma membrane / learning or memory / Extra-nuclear estrogen signaling / cell surface receptor signaling pathway / endosome 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 / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / 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 / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-0UN / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.3 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)38,4063
Polymers37,7161
Non-polymers6902
Water1,15364
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area320 Å2
ΔGint4 kcal/mol
Surface area15210 Å2
MethodPISA
Unit cell
Length a, b, c (Å)144.600, 144.600, 144.600
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number197
Space group name H-MI23
Space group name HallI223
Components on special symmetry positions
IDModelComponents
11A-1264-

HOH

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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-0UN / N-{3-[(5-chloro-2-{[2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino}pyrimidin-4-yl)oxy]phenyl}prop-2-enamide


Mass: 494.973 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H27ClN6O3 / 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.: 64 / 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: 3.34 Å3/Da / Density % sol: 63.18 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 1.5 K-Na-tartrate, 100 mM Na-MES (pH 6.0), 3.9 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: 0.915 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 24, 2018
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.915 Å / Relative weight: 1
ReflectionResolution: 2.3→41.74 Å / Num. obs: 22472 / % possible obs: 100 % / Redundancy: 20.33 % / Biso Wilson estimate: 51.53 Å2 / CC1/2: 1 / Rrim(I) all: 0.083 / Net I/σ(I): 27.45
Reflection shellResolution: 2.3→2.4 Å / Redundancy: 20.98 % / Mean I/σ(I) obs: 2.91 / Num. unique obs: 2641 / CC1/2: 0.86 / Rrim(I) all: 1.228 / % 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: 2.3→41.74 Å / SU ML: 0.2907 / Cross valid method: FREE R-VALUE / σ(F): 1.37 / Phase error: 25.8168
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2232 1124 5 %
Rwork0.1913 21344 -
obs0.1929 22468 99.98 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 67.02 Å2
Refinement stepCycle: LAST / Resolution: 2.3→41.74 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2461 0 47 64 2572
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00212575
X-RAY DIFFRACTIONf_angle_d0.60313501
X-RAY DIFFRACTIONf_chiral_restr0.0447389
X-RAY DIFFRACTIONf_plane_restr0.0036441
X-RAY DIFFRACTIONf_dihedral_angle_d14.5465942
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.3-2.410.29421410.26662679X-RAY DIFFRACTION100
2.41-2.530.29521370.24142607X-RAY DIFFRACTION99.96
2.53-2.690.2641400.23742657X-RAY DIFFRACTION100
2.69-2.90.31041380.2462628X-RAY DIFFRACTION100
2.9-3.190.23531400.2212653X-RAY DIFFRACTION100
3.19-3.650.23091410.20432674X-RAY DIFFRACTION100
3.65-4.60.18311410.15432683X-RAY DIFFRACTION100
4.61-41.740.20321460.16952763X-RAY DIFFRACTION99.9
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)
13.55702645644-2.07059546043-1.75031414773.05487933460.9168698897797.51512319739-0.009727418655040.02750301368410.3526866975730.139504852760.1536818026740.0192971110442-0.671102365997-0.3584739805530.0592806625550.5267694846770.0922067837278-0.02547663063540.4124985742390.05183872026850.491890740453134.688788338-197.037207032116.243770209
24.26876799271-2.2361273441.932830338331.44517189319-0.2394982839084.45341875107-0.3189907853190.2089808148720.4028688019280.268617322549-0.00906551402933-0.181622517301-0.7108858496030.1722402837510.2005738944540.520529896388-0.0318119010648-0.06571813413470.3892543075760.01999652164050.432880611093144.828502929-199.166787072119.037004107
34.01023560536-1.593092935791.629650952811.80986188773-0.9330154621733.34564194268-0.3053014123420.7753401588870.725400280768-0.050329054858-0.22034206111-0.298202523003-0.6216687647210.5935282863660.4161092288880.422010432983-0.121179434571-0.1080176284090.5194320678180.1499440124960.447468453132162.268894685-204.800630352119.789780469
46.29220443919-0.9632703991253.078122139860.852684197241-0.7906071534791.45103823623-0.724649748526-1.622279834060.4533478740440.4498014600190.4079682188220.204796792692-0.549090921128-0.7287891372620.2222486070060.6761208676740.1555022810860.05197712585210.85884770446-0.06163401072290.471424333654140.061160836-206.799267918133.000147672
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 697 through 752 )697 - 7521 - 52
22chain 'A' and (resid 753 through 810 )753 - 81053 - 110
33chain 'A' and (resid 811 through 977 )811 - 977111 - 277
44chain 'A' and (resid 978 through 1018 )978 - 1018278 - 317

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