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- PDB-4krp: Nanobody/VHH domain 9G8 in complex with the extracellular region ... -

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Basic information

Entry
Database: PDB / ID: 4krp
TitleNanobody/VHH domain 9G8 in complex with the extracellular region of EGFR
Components
  • Cetuximab heavy chain
  • Cetuximab light chain
  • Epidermal growth factor receptor
  • Nanobody/VHH domain 9G8
KeywordsTRANSFERASE/IMMUNE SYSTEM / cell surface receptor / glycoprotein / nanobody / VHH domain / Camelid VH domain / antibody / antigen / antibody complex / TRANSFERASE-IMMUNE SYSTEM complex
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 / 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 / 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 / SHC1 events in EGFR signaling / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / EGFR Transactivation by Gastrin / transmembrane receptor protein tyrosine kinase activity / 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 / positive regulation of epithelial cell proliferation / Signal transduction by L1 / 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 / Signaling by ERBB2 ECD mutants / receptor protein-tyrosine kinase / Signaling by ERBB2 KD Mutants / negative regulation of protein catabolic process / positive regulation of miRNA transcription / kinase binding / ruffle membrane / epidermal growth factor receptor signaling pathway / positive regulation of protein phosphorylation / cell morphogenesis / neuron differentiation / 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 / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / transmembrane signaling receptor activity / positive regulation of canonical Wnt signaling pathway / Clathrin-mediated endocytosis / PIP3 activates AKT signaling / ATPase binding / virus receptor activity / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / RAF/MAP kinase cascade / 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
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 / Growth factor receptor cysteine-rich domain superfamily / : / 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 / Immunoglobulins / Protein kinase-like domain superfamily / Immunoglobulin-like / Sandwich / Mainly Beta / Alpha Beta
Similarity search - Domain/homology
Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
Lama glama (llama)
Mus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.823 Å
AuthorsFerguson, K.M. / Schmitz, K.R.
CitationJournal: Structure / Year: 2013
Title: Structural Evaluation of EGFR Inhibition Mechanisms for Nanobodies/VHH Domains.
Authors: Schmitz, K.R. / Bagchi, A. / Roovers, R.C. / van Bergen En Henegouwen, P.M.P. / Ferguson, K.M.
History
DepositionMay 16, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 28, 2013Provider: repository / Type: Initial release
Revision 2.0Jul 29, 2020Group: Atomic model / Data collection ...Atomic model / Data collection / Database references / Derived calculations / Structure summary
Category: atom_site / chem_comp ...atom_site / chem_comp / entity / pdbx_branch_scheme / pdbx_chem_comp_identifier / pdbx_entity_branch / pdbx_entity_branch_descriptor / pdbx_entity_branch_link / pdbx_entity_branch_list / pdbx_entity_nonpoly / pdbx_nonpoly_scheme / pdbx_struct_assembly_gen / struct_asym / struct_conn / struct_ref_seq_dif / struct_site / struct_site_gen
Item: _atom_site.B_iso_or_equiv / _atom_site.Cartn_x ..._atom_site.B_iso_or_equiv / _atom_site.Cartn_x / _atom_site.Cartn_y / _atom_site.Cartn_z / _atom_site.auth_asym_id / _atom_site.auth_atom_id / _atom_site.auth_seq_id / _atom_site.label_asym_id / _atom_site.label_atom_id / _atom_site.label_entity_id / _atom_site.type_symbol / _chem_comp.name / _chem_comp.type / _pdbx_entity_nonpoly.entity_id / _pdbx_entity_nonpoly.name / _pdbx_struct_assembly_gen.asym_id_list / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.pdbx_role / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_ref_seq_dif.details
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 2.1Sep 20, 2023Group: Data collection / Database references ...Data collection / Database references / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 2.2Oct 30, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Epidermal growth factor receptor
B: Nanobody/VHH domain 9G8
C: Cetuximab light chain
D: Cetuximab heavy chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)133,01510
Polymers131,2814
Non-polymers1,7346
Water543
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)66.372, 95.841, 129.481
Angle α, β, γ (deg.)90.00, 99.95, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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Antibody , 3 types, 3 molecules BCD

#2: Antibody Nanobody/VHH domain 9G8


Mass: 15183.638 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Lama glama (llama) / Plasmid: pET22b / Production host: Escherichia coli (E. coli)
#3: Antibody Cetuximab light chain


Mass: 23159.576 Da / Num. of mol.: 1 / Fragment: Fab
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus, Homo sapiens / Plasmid: PDHL2 / Production host: Mus musculus (house mouse) / Strain (production host): SP2/0-AG15
#4: Antibody Cetuximab heavy chain


Mass: 23638.426 Da / Num. of mol.: 1 / Fragment: Fab
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus, Homo sapiens / Plasmid: PDHL2 / Production host: Mus musculus (house mouse) / Strain (production host): SP2/0-AG15

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Protein / Non-polymers , 2 types, 4 molecules A

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


Mass: 69299.812 Da / Num. of mol.: 1 / Fragment: Extracellular region (UNP residues 25-642)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EGFR, ERBB, ERBB1, HER1 / Plasmid: pFastbac / Production host: Spodoptera frugiperda (fall armyworm) / Strain (production host): SF9
References: UniProt: P00533, receptor protein-tyrosine kinase
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 3 / Source method: isolated from a natural source / Formula: H2O

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Sugars , 2 types, 6 molecules

#5: 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-Glycam 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
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}}LINUCSPDB-CARE
#6: 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.: 4
Source method: isolated from a genetically manipulated source
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 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: 3.13 Å3/Da / Density % sol: 60.65 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7
Details: 10% PEG3350, 0.1 M HEPES, pH 7.0, VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 23-ID-B / Wavelength: 0.98 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Jul 10, 2009
RadiationMonochromator: Double crystal cryo-cooled Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 2.8→50 Å / Num. all: 37840 / Num. obs: 37840 / % possible obs: 99 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 3.7 % / Rmerge(I) obs: 0.096 / Χ2: 1.276 / Net I/σ(I): 8.4
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2Diffraction-ID% possible all
2.8-2.853.10.41317751.013192.4
2.85-2.93.20.41317791.06195.3
2.9-2.963.30.39518431.043196.3
2.96-3.023.40.3418571.012198.3
3.02-3.083.50.30418701.064199.3
3.08-3.153.60.28919161.148199.7
3.15-3.233.70.24118671.128199.8
3.23-3.323.70.2119151.1371100
3.32-3.423.80.18619051.2111100
3.42-3.533.80.14818931.279199.9
3.53-3.653.80.1319251.331100
3.65-3.83.80.11119051.378199.9
3.8-3.973.80.09719101.3911100
3.97-4.183.80.07819021.2981100
4.18-4.443.90.0619261.2861100
4.44-4.793.90.05819151.4071100
4.79-5.273.80.06219051.7041100
5.27-6.033.80.05819361.461100
6.03-7.593.80.05319311.433199.9
7.59-503.70.03919651.455199.2

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
SCALEPACKdata scaling
PHASERphasing
PHENIX1.8.2_1309refinement
PDB_EXTRACT3.11data extraction
JBluIce-EPICSdata collection
HKL-3000data reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1YY9 and 4KRN

1yy9

4krn


Resolution: 2.823→44.46 Å / Occupancy max: 1 / Occupancy min: 1 / FOM work R set: 0.7718 / SU ML: 0.38 / σ(F): 1.36 / Phase error: 29.58 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2627 1889 5 %RANDOM
Rwork0.2151 ---
obs0.2175 37811 98.04 %-
all-37811 --
Solvent computationShrinkage radii: 1.1 Å / VDW probe radii: 1.2 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 203.13 Å2 / Biso mean: 68.5907 Å2 / Biso min: 9.03 Å2
Refinement stepCycle: LAST / Resolution: 2.823→44.46 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7745 0 112 3 7860
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0058063
X-RAY DIFFRACTIONf_angle_d0.92611050
X-RAY DIFFRACTIONf_chiral_restr0.0781283
X-RAY DIFFRACTIONf_plane_restr0.0041426
X-RAY DIFFRACTIONf_dihedral_angle_d13.6642715
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 13

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.823-2.89960.33021070.30892302240981
2.8996-2.98490.36721470.29152664281196
2.9849-3.08130.3721500.27792760291099
3.0813-3.19140.38751410.288827842925100
3.1914-3.31910.31641300.256328482978100
3.3191-3.47010.30181350.237727782913100
3.4701-3.6530.24881450.220328382983100
3.653-3.88170.29251620.210427912953100
3.8817-4.18120.24511560.189128132969100
4.1812-4.60160.20131470.16128142961100
4.6016-5.26660.20661550.1628122967100
5.2666-6.63180.23931540.2128392993100
6.6318-44.46510.23651600.21972879303999

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