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- PDB-7lfr: Crystal structure of the epidermal growth factor receptor extrace... -

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Basic information

Entry
Database: PDB / ID: 7lfr
TitleCrystal structure of the epidermal growth factor receptor extracellular region with R84K mutation in complex with epiregulin crystallized with spermine
Components
  • Epidermal growth factor receptor
  • Proepiregulin
KeywordsSIGNALING PROTEIN / receptor / epiregulin / glioblastoma / cancer / mutation / extracellular / asymmetric / dimer / ErbB1 / EGFR
Function / homology
Function and homology information


primary follicle stage / ovarian cumulus expansion / luteinizing hormone signaling pathway / negative regulation of smooth muscle cell differentiation / ERBB4-ERBB4 signaling pathway / ovulation / female meiotic nuclear division / keratinocyte proliferation / ERBB2-ERBB4 signaling pathway / transmembrane receptor protein tyrosine kinase activator activity ...primary follicle stage / ovarian cumulus expansion / luteinizing hormone signaling pathway / negative regulation of smooth muscle cell differentiation / ERBB4-ERBB4 signaling pathway / ovulation / female meiotic nuclear division / keratinocyte proliferation / ERBB2-ERBB4 signaling pathway / transmembrane receptor protein tyrosine kinase activator activity / oocyte maturation / PI3K events in ERBB4 signaling / positive regulation of innate immune response / multivesicular body, internal vesicle lumen / negative regulation of cardiocyte differentiation / Shc-EGFR complex / mRNA transcription / positive regulation of protein kinase C signaling / Inhibition of Signaling by Overexpressed EGFR / EGFR interacts with phospholipase C-gamma / epidermal growth factor receptor activity / epidermal growth factor binding / response to UV-A / epidermal growth factor receptor binding / regulation of peptidyl-tyrosine phosphorylation / PLCG1 events in ERBB2 signaling / ERBB2-EGFR signaling pathway / ERBB2 Activates PTK6 Signaling / PTK6 promotes HIF1A stabilization / Signaling by EGFR / intracellular vesicle / negative regulation of epidermal growth factor receptor signaling pathway / ERBB2 Regulates Cell Motility / positive regulation of protein kinase activity / Developmental Lineage of Mammary Gland Myoepithelial Cells / positive regulation of cell division / keratinocyte differentiation / protein insertion into membrane / 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 / MAP kinase kinase kinase activity / GAB1 signalosome / anatomical structure morphogenesis / protein tyrosine kinase activator activity / SHC1 events in ERBB4 signaling / Nuclear signaling by ERBB4 / ossification / positive regulation of G1/S transition of mitotic cell cycle / Signaling by ERBB2 / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / animal organ morphogenesis / positive regulation of mitotic nuclear division / transmembrane receptor protein tyrosine kinase activity / positive regulation of epithelial cell proliferation / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / positive regulation of smooth muscle cell proliferation / EGFR Transactivation by Gastrin / GRB2 events in ERBB2 signaling / positive regulation of fibroblast proliferation / SHC1 events in ERBB2 signaling / cellular response to epidermal growth factor stimulus / positive regulation of DNA repair / positive regulation of DNA replication / basal plasma membrane / cellular response to amino acid stimulus / positive regulation of cytokine production / wound healing / phosphatidylinositol 3-kinase/protein kinase B signal transduction / Signal transduction by L1 / cellular response to estradiol stimulus / positive regulation of protein localization to plasma membrane / growth factor activity / negative regulation of protein catabolic process / NOTCH3 Activation and Transmission of Signal to the Nucleus / clathrin-coated endocytic vesicle membrane / cell-cell adhesion / Signaling by ERBB2 TMD/JMD mutants / EGFR downregulation / Constitutive Signaling by EGFRvIII / receptor protein-tyrosine kinase / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / negative regulation of epithelial cell proliferation / positive regulation of interleukin-6 production / positive regulation of miRNA transcription / cell junction / positive regulation of protein phosphorylation / response to peptide hormone / epidermal growth factor receptor signaling pathway / kinase binding / ruffle membrane / cytokine-mediated signaling pathway / Downregulation of ERBB2 signaling / Constitutive Signaling by Aberrant PI3K in Cancer / HCMV Early Events
Similarity search - Function
: / Epiregulin C-terminal domain / Hormone Receptor, Insulin-like Growth Factor Receptor 1; Chain A domain 2 / Hormone Receptor, Insulin-like Growth Factor Receptor 1; Chain A, domain 2 / 24 nucleotide stem-loop, u2 snrnp hairpin iv. U2 a'; Chain A / Receptor L-domain / Alpha-Beta Horseshoe / : / Epidermal growth factor receptor transmembrane-juxtamembrane segment / Tyrosine protein kinase, EGF/ERB/XmrK receptor ...: / Epiregulin C-terminal domain / Hormone Receptor, Insulin-like Growth Factor Receptor 1; Chain A domain 2 / Hormone Receptor, Insulin-like Growth Factor Receptor 1; Chain A, domain 2 / 24 nucleotide stem-loop, u2 snrnp hairpin iv. U2 a'; Chain A / Receptor L-domain / Alpha-Beta Horseshoe / : / 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 / EGF-like domain profile. / Growth factor receptor cysteine-rich domain superfamily / EGF-like domain signature 1. / : / EGF-like domain signature 2. / EGF-like domain / Ribbon / 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 / Mainly Beta / Alpha Beta
Similarity search - Domain/homology
beta-D-mannopyranose / alpha-D-mannopyranose / Proepiregulin / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.2 Å
AuthorsHu, C. / Leche II, C.A. / Stayrook, S.E. / Ferguson, K.M. / Lemmon, M.A.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)R01CA198164 United States
CitationJournal: Nature / Year: 2022
Title: Glioblastoma mutations alter EGFR dimer structure to prevent ligand bias.
Authors: Hu, C. / Leche 2nd, C.A. / Kiyatkin, A. / Yu, Z. / Stayrook, S.E. / Ferguson, K.M. / Lemmon, M.A.
History
DepositionJan 18, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 17, 2021Provider: repository / Type: Initial release
Revision 1.1Jun 1, 2022Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.3Oct 30, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Epidermal growth factor receptor
B: Epidermal growth factor receptor
C: Proepiregulin
D: Proepiregulin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)124,59713
Polymers122,5684
Non-polymers2,0309
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: SAXS
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
A: Epidermal growth factor receptor
C: Proepiregulin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)62,0685
Polymers61,2842
Non-polymers7853
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3910 Å2
ΔGint1 kcal/mol
Surface area25050 Å2
MethodPISA
3
B: Epidermal growth factor receptor
D: Proepiregulin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)62,5298
Polymers61,2842
Non-polymers1,2456
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4440 Å2
ΔGint8 kcal/mol
Surface area25240 Å2
MethodPISA
Unit cell
Length a, b, c (Å)77.593, 87.206, 198.013
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

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Protein / Protein/peptide , 2 types, 4 molecules ABCD

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


Mass: 55803.461 Da / Num. of mol.: 2 / Mutation: R84K
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: Protein/peptide Proepiregulin


Mass: 5480.307 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EREG / Production host: Drosophila melanogaster (fruit fly) / References: UniProt: O14944

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Sugars , 4 types, 9 molecules

#3: Polysaccharide beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 383.349 Da / Num. of mol.: 1 / Source method: obtained synthetically
DescriptorTypeProgram
DManpb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/2,2,1/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5]/1-2/a4-b1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-Manp]{}}LINUCSPDB-CARE
#4: Sugar
ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0
#5: Sugar ChemComp-MAN / alpha-D-mannopyranose / alpha-D-mannose / D-mannose / mannose


Type: D-saccharide, alpha linking / Mass: 180.156 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C6H12O6
IdentifierTypeProgram
DManpaCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
a-D-mannopyranoseCOMMON NAMEGMML 1.0
a-D-ManpIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
ManSNFG CARBOHYDRATE SYMBOLGMML 1.0
#6: Sugar ChemComp-BMA / beta-D-mannopyranose / beta-D-mannose / D-mannose / mannose


Type: D-saccharide, beta linking / Mass: 180.156 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H12O6
IdentifierTypeProgram
DManpbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
b-D-mannopyranoseCOMMON NAMEGMML 1.0
b-D-ManpIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
ManSNFG CARBOHYDRATE SYMBOLGMML 1.0

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Details

Has ligand of interestN
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: 2.64 Å3/Da / Density % sol: 53 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 8 mg/ml protein, 100 mM HEPES (pH 7.5), 12% PEG3350, 10 mM spermine tetrahydrochloride

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 23-ID-B / Wavelength: 1.0332 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Feb 14, 2020 / Details: Undulator
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0332 Å / Relative weight: 1
ReflectionResolution: 3.2→99.006 Å / Num. obs: 22984 / % possible obs: 99.8 % / Redundancy: 8.4 % / Rpim(I) all: 0.073 / Rrim(I) all: 0.215 / Rsym value: 0.202 / Net I/av σ(I): 3.1 / Net I/σ(I): 9 / Num. measured all: 193914
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique obsRpim(I) allRrim(I) allRsym valueNet I/σ(I) obs% possible all
3.2-3.378.61.4190.52818532710.5111.5111.4191.798.7
3.37-3.578.80.9060.82719131010.3250.9630.9062.8100
3.57-3.828.30.6031.22454729630.2230.6440.6034.3100
3.82-4.138.60.3621.82364727460.1310.3860.3627.1100
4.13-4.528.90.2252.72262325470.0790.2380.22510.4100
4.52-5.058.50.1693.41966123040.0610.180.16912.9100
5.05-5.847.90.154.11646020710.0560.160.1512100
5.84-7.158.50.1135.51490317630.0410.120.11314.4100
7.15-10.117.80.0669.71087413890.0250.0710.06620.5100
10.11-43.60570.0371658238290.0150.040.03730.298.9

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Processing

Software
NameVersionClassification
PHENIX1.18.2_3874refinement
PDB_EXTRACT3.27data extraction
XDS20200417data reduction
SCALA3.3.22data scaling
PHASER2.8.3phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5WB7

5wb7


Resolution: 3.2→43.6 Å / SU ML: 0.47 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 30.43 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.3026 1114 4.86 %0
Rwork0.2498 21790 --
obs0.2523 22904 99.69 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 170.45 Å2 / Biso mean: 92.041 Å2 / Biso min: 40.83 Å2
Refinement stepCycle: final / Resolution: 3.2→43.6 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8290 0 128 0 8418
Biso mean--104.67 --
Num. residues----1093
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 8

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
3.2-3.340.37451280.31872653278198
3.34-3.520.35371370.30926792816100
3.52-3.740.3581420.286726802822100
3.74-4.030.32321470.262626872834100
4.03-4.430.30041480.23326982846100
4.43-5.070.28821440.218527152859100
5.07-6.390.23021370.254527712908100
6.39-43.60.31031310.235829073038100

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