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- PDB-9ghr: Crystal Structure of EGFR-WT in Complex with Covalent Compound 10n -

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Basic information

Entry
Database: PDB / ID: 9ghr
TitleCrystal Structure of EGFR-WT in Complex with Covalent Compound 10n
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 / intracellular vesicle / cerebral cortex cell migration / 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 / double-stranded DNA binding / sperm midpiece / 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: 2.1 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.L. / 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

Downloads & links

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Assembly

Deposited unit
A: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,5903
Polymers37,8761
Non-polymers7142
Water1,820101
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area300 Å2
ΔGint3 kcal/mol
Surface area14600 Å2
Unit cell
Length a, b, c (Å)144.950, 144.950, 144.950
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-A1ILN / (~{N}~{E})-2-isoquinolin-4-yl-~{N}-[3-[(3~{R})-1-propanoylazepan-3-yl]-1~{H}-benzimidazol-2-ylidene]pyridine-4-carboxamide


Mass: 518.609 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C31H30N6O2 / 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.: 101 / 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: 3.35 Å3/Da / Density % sol: 63.29 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 1.4 K-Na-tartrate, 100 mM Na-MES (pH 7.0), 5.7 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: 1 Å
DetectorType: DECTRIS EIGER2 X 16M / Detector: PIXEL / Date: Sep 19, 2021
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.1→38.74 Å / Num. obs: 29638 / % possible obs: 100 % / Redundancy: 10.53 % / Biso Wilson estimate: 47.78 Å2 / CC1/2: 0.998 / Rrim(I) all: 0.087 / Net I/σ(I): 15.99
Reflection shellResolution: 2.1→2.2 Å / Redundancy: 10.98 % / Mean I/σ(I) obs: 3.32 / Num. unique obs: 3818 / CC1/2: 0.887 / Rrim(I) all: 0.771 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
PHENIX1.20.1_4487refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.1→38.74 Å / SU ML: 0.2905 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 23.5699
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2017 1482 5 %
Rwork0.181 28151 -
obs0.182 29633 99.98 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 53.99 Å2
Refinement stepCycle: LAST / Resolution: 2.1→38.74 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2381 0 51 101 2533
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00282506
X-RAY DIFFRACTIONf_angle_d0.54323410
X-RAY DIFFRACTIONf_chiral_restr0.0444382
X-RAY DIFFRACTIONf_plane_restr0.0048426
X-RAY DIFFRACTIONf_dihedral_angle_d12.6752915
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.1-2.170.35261330.29442541X-RAY DIFFRACTION100
2.17-2.250.24771350.2332554X-RAY DIFFRACTION100
2.25-2.340.26051320.22172518X-RAY DIFFRACTION100
2.34-2.440.30041340.21382548X-RAY DIFFRACTION100
2.44-2.570.24741330.20812524X-RAY DIFFRACTION100
2.57-2.730.2531350.22792563X-RAY DIFFRACTION100
2.73-2.940.24961330.22782526X-RAY DIFFRACTION100
2.94-3.240.26051350.20912571X-RAY DIFFRACTION100
3.24-3.710.19561360.1792566X-RAY DIFFRACTION100
3.71-4.670.14761360.13682589X-RAY DIFFRACTION100
4.67-38.740.16521400.15952651X-RAY DIFFRACTION99.82
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)
10.5687461794780.006004192365890.1905529837271.34388829441-0.04841844341930.6897005914620.130569629016-0.2563275789490.409534464529-0.1272619846960.01617118616980.07427749761670.1472095548050.6150085004450.004438788289780.547222130625-0.103706559334-0.03047531883510.456421350677-0.02494689368730.53238815420310.2790661674-55.132727829533.4837511025
21.078817039710.610405115998-0.06645404418360.9949611917110.1075396230122.04300770168-0.0679617243287-0.0420016249640.235925644384-0.01398652917910.0546228176987-0.0984687574295-0.3195106731960.0156665877353-0.04317067427410.456820369483-0.0604163337877-0.06409013474990.4619594698150.01689313960810.4560946220925.31489926832-52.748004500229.9636914295
33.198013389911.24635229580.2859369063011.652636389290.3208729482210.682088470741-0.1592811584850.1916004113270.158607083901-0.1357220063340.0798013760568-0.0130689087685-0.2318175408430.124879252740.1538912915930.385498147465-0.0500021807258-0.03574025453250.4391487564320.02348395306710.337691751244-6.8569552496-60.556192064820.2086190034
42.224470290940.169390107953-0.7162066294470.9698457204331.391988833233.159544146960.026152378105-0.8887872383840.09244395329550.284830454831-0.192374518842-0.271225735725-0.2063595470290.2856341914990.2089682040490.601643807171-0.0143727755191-0.06803504348030.605972586308-0.03673929409160.387138834517-13.2309137218-55.915351156939.6644115927
50.5255554253650.6508463297760.6510822281441.798506337591.267899166381.18324033988-0.22396696194-0.3651451090230.1839319019220.336979925002-0.2126172325690.314640784656-0.2136202028230.2779339698380.2975818818570.5067634838890.00191816134155-0.04815216777670.576729537377-0.1567779186790.616755580054-21.7218080116-51.636676159432.6375189757
62.827967591930.07955629407320.6600029869921.976461402210.5173779485181.92955196799-0.1280931478540.07812324391270.30118211705-0.0516952085077-0.1802408711790.0724334135505-0.219266692297-0.2002443720560.2276305844380.372457492549-0.0271716498109-0.04844817877030.447781115885-0.01934858993740.382055400643-22.2135595089-62.14239694219.1522585996
70.423680908143-0.4844352446250.1270623574851.38856759653-0.434754639892.99994448159-0.2866008706520.420913945992-0.441233476597-0.2757290407930.143572790556-0.187197229716-0.4161799766840.216029267662-0.1289227921360.655469076085-0.1351549336820.00978780476570.7057875782740.07076322073090.56881635318610.0950631494-63.663945155218.0320775301
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 786 )718 - 78622 - 86
33chain 'A' and (resid 787 through 853 )787 - 85387 - 153
44chain 'A' and (resid 854 through 873 )854 - 873154 - 173
55chain 'A' and (resid 874 through 892 )874 - 892174 - 192
66chain 'A' and (resid 893 through 986 )893 - 986193 - 286
77chain 'A' and (resid 987 through 1019 )987 - 1019287 - 304

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