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- PDB-9ghu: Crystal Structure of EGFR-WT in Complex with Covalent Compound 10f -

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Basic information

Entry
Database: PDB / ID: 9ghu
TitleCrystal Structure of EGFR-WT in Complex with Covalent Compound 10f
ComponentsEpidermal growth factor receptor
KeywordsTRANSFERASE / EGFR / WT / Exon20 / covalent
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 / epidermal growth factor receptor activity / EGFR interacts with phospholipase C-gamma / 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 / epidermal growth factor receptor activity / EGFR interacts with phospholipase C-gamma / regulation of peptidyl-tyrosine phosphorylation / epidermal growth factor binding / response to UV-A / ubiquitin-dependent endocytosis / PLCG1 events in ERBB2 signaling / morphogenesis of an epithelial fold / PTK6 promotes HIF1A stabilization / ERBB2 Activates PTK6 Signaling / digestive tract morphogenesis / ERBB2-EGFR signaling pathway / Signaling by EGFR / eyelid development in camera-type eye / cerebral cortex cell migration / intracellular vesicle / Developmental Lineage of Mammary Gland Myoepithelial Cells / ERBB2 Regulates Cell Motility / protein insertion into membrane / Respiratory syncytial virus (RSV) attachment and entry / protein tyrosine kinase activator activity / Signaling by ERBB4 / negative regulation of epidermal growth factor receptor signaling pathway / PI3K events in ERBB2 signaling / positive regulation of peptidyl-serine phosphorylation / positive regulation of phosphorylation / hair follicle development / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / MAP kinase kinase kinase activity / GAB1 signalosome / embryonic placenta development / positive regulation of G1/S transition of mitotic cell cycle / salivary gland morphogenesis / xenobiotic transport / positive regulation of epidermal growth factor receptor signaling pathway / Signaling by ERBB2 / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / GRB2 events in EGFR signaling / transmembrane receptor protein tyrosine kinase activity / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / GRB2 events in ERBB2 signaling / SHC1 events in ERBB2 signaling / epithelial cell proliferation / ossification / cellular response to epidermal growth factor stimulus / basal plasma membrane / positive regulation of DNA replication / positive regulation of epithelial cell proliferation / positive regulation of DNA repair / Signal transduction by L1 / positive regulation of protein localization to plasma membrane / sperm end piece / cellular response to estradiol stimulus / NOTCH3 Activation and Transmission of Signal to the Nucleus / cellular response to amino acid stimulus / phosphatidylinositol 3-kinase/protein kinase B signal transduction / clathrin-coated endocytic vesicle membrane / EGFR downregulation / Signaling by ERBB2 TMD/JMD mutants / Constitutive Signaling by EGFRvIII / receptor protein-tyrosine kinase / Signaling by ERBB2 ECD mutants / cell-cell adhesion / negative regulation of protein catabolic process / Signaling by ERBB2 KD Mutants / positive regulation of protein phosphorylation / positive regulation of miRNA transcription / Downregulation of ERBB2 signaling / kinase binding / positive regulation of fibroblast proliferation / ruffle membrane / epidermal growth factor receptor signaling pathway / cell morphogenesis / neuron differentiation / Constitutive Signaling by Aberrant PI3K in Cancer / HCMV Early Events / actin filament binding / cell junction / transmembrane signaling receptor activity / positive regulation of canonical Wnt signaling pathway / PIP3 activates AKT signaling / Cargo recognition for clathrin-mediated endocytosis / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / Clathrin-mediated endocytosis / sperm principal piece / ATPase binding / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / virus receptor activity / RAF/MAP kinase cascade / positive regulation of cell growth / protein tyrosine kinase activity / sperm midpiece / double-stranded DNA binding / early 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 / 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
: / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.25 Å
AuthorsNiggenaber, J. / Mueller, M.P. / Rauh, D.
Funding support Germany, European Union, 4items
OrganizationGrant numberCountry
German Federal Ministry for Education and Research01ZX2201B Germany
European Regional Development FundEFRE-800400European Union
Other privateEx-2021-0033
Other governmentNW21-062C
CitationJournal: to be published
Title: Selective Targeting of EGFR-Exon20 Insertion Mutations in Non-Small Cell Lung Cancer with Nazartinib and BI-4020 Inspired Hybrid Inhibitors
Authors: Grabe, T. / Jeyakumar, K. / Niggenaber, J. / Grabe, B. / Koska, S. / Zischinsky, M. / Unger, A. / Weisner, J. / Arndt, A. / Mueller, M.P. / Rauh, D.
History
DepositionAug 16, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 4, 2026Provider: repository / Type: Initial release

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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)38,5573
Polymers37,8761
Non-polymers6812
Water1,27971
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area290 Å2
ΔGint3 kcal/mol
Surface area14660 Å2
Unit cell
Length a, b, c (Å)145.930, 145.930, 145.930
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 / Proto-oncogene c-ErbB-1 / Receptor tyrosine-protein kinase erbB-1


Mass: 37875.754 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-A1ILK / (~{N}~{E})-2-(1,3-dimethylpyrazol-4-yl)-~{N}-[3-[(3~{R})-1-propanoylazepan-3-yl]-1~{H}-benzimidazol-2-ylidene]pyridine-4-carboxamide


Mass: 485.581 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H31N7O2 / 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.: 71 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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: 293 K / Method: vapor diffusion, hanging drop
Details: 1.4 K-Na-tartrate, 100 mM Na-MES (pH 7.0), 4.5 mg/mL EGFR-WT (im 100 mM NaCl, 25 mM Tris-HCl, 10 % glycerol, 1 mM TCEP, pH 8.0, 1 ul reservoir + 1 ul solution) Soaking-Experiment

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.9188 Å
DetectorType: DECTRIS EIGER2 X 16M / Detector: PIXEL / Date: Feb 10, 2023
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9188 Å / Relative weight: 1
ReflectionResolution: 2.25→46.15 Å / Num. obs: 24649 / % possible obs: 99.9 % / Redundancy: 10.08 % / Biso Wilson estimate: 56.01 Å2 / CC1/2: 0.999 / Rrim(I) all: 0.085 / Net I/σ(I): 15.82
Reflection shellResolution: 2.25→2.35 Å / Redundancy: 10.49 % / Mean I/σ(I) obs: 1.84 / Num. unique obs: 1570 / CC1/2: 0.661 / Rrim(I) all: 1.479 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
PDB_EXTRACTdata extraction
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.25→46.15 Å / SU ML: 0.3077 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 24.8356
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2184 1233 5 %
Rwork0.1837 23408 -
obs0.1855 24641 99.92 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 61.38 Å2
Refinement stepCycle: LAST / Resolution: 2.25→46.15 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2355 0 48 72 2475
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00272480
X-RAY DIFFRACTIONf_angle_d0.55053376
X-RAY DIFFRACTIONf_chiral_restr0.0441380
X-RAY DIFFRACTIONf_plane_restr0.0054422
X-RAY DIFFRACTIONf_dihedral_angle_d12.8087902
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.25-2.340.29891370.29172597X-RAY DIFFRACTION100
2.34-2.450.29791350.24892566X-RAY DIFFRACTION100
2.45-2.580.29371360.22942587X-RAY DIFFRACTION100
2.58-2.740.28521350.24052562X-RAY DIFFRACTION100
2.74-2.950.25641370.24632611X-RAY DIFFRACTION99.89
2.95-3.240.25511360.22152580X-RAY DIFFRACTION99.96
3.25-3.710.25651370.1872609X-RAY DIFFRACTION100
3.72-4.680.17331380.14172616X-RAY DIFFRACTION99.96
4.68-46.150.1741420.15742680X-RAY DIFFRACTION99.47
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)
12.74205048399-0.0732708080582-0.1639105067281.027560671970.3742633000911.778143987420.0716482867650.04440913520250.0347060602940.2604340857130.112736452101-0.4094816858720.6384047111110.104687871839-0.1440201960140.538252403150.067999696238-0.02902618221680.6085728138110.05529950492770.651393198488-55.4915024562-10.115491116933.8102690928
24.779124836871.582351799981.668479049834.508544232952.342092440943.105086180160.268214660438-0.273418345926-0.434418380772-0.0399736487632-0.239204278607-0.7583328393340.2592198212050.277182969722-0.08596707954350.569009613570.1058137867790.02362136094680.5879368852750.06285267239140.529691324786-51.2329233048-8.2255734119125.2218723703
30.795237840017-0.4861543230851.39683254681.6349495047-0.9530896277852.81421629527-0.003781115628540.0463023805361-0.0672331087714-0.054907943490.0119020936305-0.25896322994-0.1280852794840.3808456883930.00779926522670.5711168498220.0655226372580.0008775872346110.6007800065930.06030281180970.546412130509-54.6458867322-1.8013989493834.8395108127
41.7336160888-0.45260194085-0.2390211005594.10216277946-0.1280428162410.3506205308460.19480365460.3408151404230.0761961138817-0.677178099944-0.276390506293-0.5520503536260.184898304464-0.04204315695890.006346321537610.5834732877560.1167044385160.09750390187860.6132893833660.02845075050360.471188445228-56.07345246583.8122507091214.7941843413
52.98923681985-1.191768271230.3845365929623.24407250886-0.4312942910941.22891639897-0.0176003277151-0.171649424287-0.02080445530710.10160827576-0.0626849189275-0.04491436420750.1942803004770.1876919029560.04968997268510.4731330589390.03384870529480.01788044023190.4431125030320.02371789701740.466948496362-64.05019265128.6732068403923.8326565564
61.642555034910.7503187243411.881669668833.231604574970.6677223922382.58713427555-0.209979039573-0.709232933797-0.0835836584890.5507663103370.1346774911320.0112178564575-0.3255406763980.273703398899-0.09137366817480.7128108310810.0776637176122-0.02985478354330.7746309350330.07023845243910.544206129925-56.662697083713.476564239739.9189257826
71.988696153260.3147836527840.5193402252373.19562769851-0.02706839728172.57989750598-0.103848030136-0.15280590280.134102609790.138119396258-0.114395894707-0.289129758528-0.2063178126620.175980130740.1768821407460.4709173299820.0396413555552-0.0239500914730.4485985551110.03778686502080.447050229843-60.515057081222.687124105322.9990360512
80.401561009169-1.29185735440.9678816946338.91931957815-3.175057979272.286799407660.2347599478230.0405759216721-0.281111729727-1.00213444443-0.3238905725930.0858565335320.6505882950330.1633009847840.1158964110980.6283843692850.1006939198870.07137502008760.631131413275-0.01528318062130.544477538094-65.5854700005-2.4915729344315.5061612936
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 717 )697 - 7171 - 21
22chain 'A' and (resid 718 through 752 )718 - 75222 - 53
33chain 'A' and (resid 753 through 786 )753 - 78654 - 87
44chain 'A' and (resid 787 through 810 )787 - 81088 - 111
55chain 'A' and (resid 811 through 853 )811 - 853112 - 154
66chain 'A' and (resid 854 through 873 )854 - 873155 - 174
77chain 'A' and (resid 874 through 977 )874 - 977175 - 278
88chain 'A' and (resid 978 through 1020 )978 - 1020279 - 303

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