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

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Basic information

Entry
Database: PDB / ID: 7len
TitleCrystal structure of the epidermal growth factor receptor extracellular region with R84K mutation in complex with epiregulin crystallized with trehalose
Components
  • Isoform 4 of Epidermal growth factor receptor
  • Proepiregulin
KeywordsSIGNALING PROTEIN / receptor / epiregulin / glioblastoma / cancer / mutation / extracellular / asymmetric / dimer / ErbB1 / EGFR
Function / homology
Function and homology information


luteinizing hormone signaling pathway / ovulation / ovarian cumulus expansion / ERBB4-ERBB4 signaling pathway / negative regulation of smooth muscle cell differentiation / ERBB2-ERBB4 signaling pathway / primary follicle stage / female meiotic nuclear division / PI3K events in ERBB4 signaling / transmembrane receptor protein tyrosine kinase activator activity ...luteinizing hormone signaling pathway / ovulation / ovarian cumulus expansion / ERBB4-ERBB4 signaling pathway / negative regulation of smooth muscle cell differentiation / ERBB2-ERBB4 signaling pathway / primary follicle stage / female meiotic nuclear division / PI3K events in ERBB4 signaling / transmembrane receptor protein tyrosine kinase activator activity / positive regulation of innate immune response / mRNA transcription / oocyte maturation / multivesicular body, internal vesicle lumen / negative regulation of cardiocyte differentiation / epidermal growth factor receptor binding / 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 / 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 / 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 / positive regulation of protein kinase activity / protein tyrosine kinase activator activity / Respiratory syncytial virus (RSV) attachment and entry / positive regulation of cell division / Signaling by ERBB4 / PI3K events in ERBB2 signaling / keratinocyte proliferation / positive regulation of phosphorylation / anatomical structure morphogenesis / positive regulation of peptidyl-serine phosphorylation / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / SHC1 events in ERBB4 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 / Nuclear signaling by ERBB4 / keratinocyte differentiation / Signaling by ERBB2 / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / transmembrane receptor protein tyrosine kinase activity / EGFR Transactivation by Gastrin / positive regulation of smooth muscle cell proliferation / positive regulation of mitotic nuclear division / GRB2 events in ERBB2 signaling / ossification / SHC1 events in ERBB2 signaling / basal plasma membrane / positive regulation of DNA repair / cellular response to epidermal growth factor stimulus / positive regulation of cytokine production / animal organ morphogenesis / positive regulation of DNA replication / epithelial cell proliferation / positive regulation of epithelial cell proliferation / Signal transduction by L1 / positive regulation of protein localization to plasma membrane / NOTCH3 Activation and Transmission of Signal to the Nucleus / cellular response to amino acid stimulus / growth factor activity / phosphatidylinositol 3-kinase/protein kinase B signal transduction / cellular response to estradiol stimulus / EGFR downregulation / wound healing / clathrin-coated endocytic vesicle membrane / Signaling by ERBB2 TMD/JMD mutants / Constitutive Signaling by EGFRvIII / cell-cell adhesion / response to peptide hormone / receptor protein-tyrosine kinase / Signaling by ERBB2 ECD mutants / negative regulation of protein catabolic process / Signaling by ERBB2 KD Mutants / positive regulation of interleukin-6 production / positive regulation of miRNA transcription / kinase binding / ruffle membrane / Downregulation of ERBB2 signaling / epidermal growth factor receptor signaling pathway
Similarity search - Function
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 / : / Epidermal growth factor receptor transmembrane-juxtamembrane segment / Alpha-Beta Horseshoe / Tyrosine protein kinase, EGF/ERB/XmrK receptor / Growth factor receptor domain 4 / Growth factor receptor domain IV ...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 / : / Epidermal growth factor receptor transmembrane-juxtamembrane segment / Alpha-Beta Horseshoe / 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 / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / 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
Proepiregulin / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.9 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 14, 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: Isoform 4 of Epidermal growth factor receptor
B: Isoform 4 of Epidermal growth factor receptor
C: Proepiregulin
D: Proepiregulin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)127,32411
Polymers123,9494
Non-polymers3,3757
Water00
1
A: Isoform 4 of Epidermal growth factor receptor
C: Proepiregulin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)63,3695
Polymers61,9742
Non-polymers1,3943
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4650 Å2
ΔGint11 kcal/mol
Surface area25130 Å2
MethodPISA
2
B: Isoform 4 of Epidermal growth factor receptor
D: Proepiregulin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)63,9556
Polymers61,9742
Non-polymers1,9814
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5300 Å2
ΔGint24 kcal/mol
Surface area25340 Å2
MethodPISA
Unit cell
Length a, b, c (Å)77.737, 86.600, 197.795
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 Isoform 4 of Epidermal growth factor receptor / Proto-oncogene c-ErbB-1 / Receptor tyrosine-protein kinase erbB-1


Mass: 56494.184 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 , 5 types, 7 molecules

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


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}LINUCSPDB-CARE
#4: Polysaccharide alpha-D-mannopyranose-(1-3)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1- ...alpha-D-mannopyranose-(1-3)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 748.682 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-3DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/3,4,3/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1122h-1a_1-5]/1-1-2-3/a4-b1_b4-c1_c3-d1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(3+1)][a-D-Manp]{}}}}LINUCSPDB-CARE
#5: Polysaccharide 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-6)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-6DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a6-b1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(6+1)][b-D-GlcpNAc]{}}LINUCSPDB-CARE
#6: Polysaccharide alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2- ...alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 910.823 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-3[DManpa1-6]DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/3,5,4/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1122h-1a_1-5]/1-1-2-3-3/a4-b1_b4-c1_c3-d1_c6-e1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(3+1)][a-D-Manp]{}[(6+1)][a-D-Manp]{}}}}LINUCSPDB-CARE
#7: 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.: 2 / 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

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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, with 3% (w/v) D-(+)-trehalose dihydrate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 23-ID-B / Wavelength: 1.03318 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: 1.03318 Å / Relative weight: 1
ReflectionResolution: 2.9→43.48 Å / Num. obs: 30250 / % possible obs: 99.8 % / Observed criterion σ(F): -3 / Observed criterion σ(I): -3 / Redundancy: 6.7 % / Biso Wilson estimate: 68 Å2 / CC1/2: 0.997 / Rmerge(I) obs: 0.134 / Rpim(I) all: 0.056 / Rrim(I) all: 0.146 / Rsym value: 0.134 / Net I/σ(I): 10.9
Reflection shellResolution: 2.9→2.98 Å / Redundancy: 6.5 % / Rmerge(I) obs: 1.349 / Mean I/σ(I) obs: 1.3 / Num. unique obs: 4148 / CC1/2: 0.489 / Rpim(I) all: 0.572 / Rrim(I) all: 1.467 / Rsym value: 1.349 / % possible all: 97.4

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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: 2.9→43.48 Å / SU ML: 0.5 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 31.46 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2946 1473 4.87 %
Rwork0.2368 28777 -
obs0.2396 30250 99.78 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 204.53 Å2 / Biso mean: 86.6232 Å2 / Biso min: 35.41 Å2
Refinement stepCycle: final / Resolution: 2.9→43.48 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8200 0 223 0 8423
Biso mean--123.93 --
Num. residues----1093
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 11

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.9-30.4851440.38922539268398
3-3.10.37551250.32825552680100
3.1-3.230.36231390.287625932732100
3.23-3.370.34591240.29525732697100
3.37-3.550.36341330.267625962729100
3.55-3.770.30921390.25725862725100
3.77-4.070.28851360.236425912727100
4.07-4.470.25451280.213126282756100
4.47-5.120.25311490.199426242773100
5.12-6.450.33491200.235326882808100
6.45-43.480.25271360.213528042940100

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