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- PDB-4kro: Nanobody/VHH domain EgA1 in complex with the extracellular region... -

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Basic information

Entry
Database: PDB / ID: 4kro
TitleNanobody/VHH domain EgA1 in complex with the extracellular region of EGFR
Components
  • Cetuximab heavy chain
  • Cetuximab light chain
  • Epidermal growth factor receptor
  • Nanobody/VHH domain EgA1
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


response to hydroxyisoflavone / multivesicular body, internal vesicle lumen / positive regulation of protein kinase C activity / positive regulation of prolactin secretion / negative regulation of cardiocyte differentiation / diterpenoid metabolic process / Shc-EGFR complex / ovulation cycle / Inhibition of Signaling by Overexpressed EGFR / epidermal growth factor receptor activity ...response to hydroxyisoflavone / multivesicular body, internal vesicle lumen / positive regulation of protein kinase C activity / positive regulation of prolactin secretion / negative regulation of cardiocyte differentiation / diterpenoid metabolic process / Shc-EGFR complex / ovulation cycle / Inhibition of Signaling by Overexpressed EGFR / epidermal growth factor receptor activity / EGFR interacts with phospholipase C-gamma / positive regulation of mucus secretion / epidermal growth factor binding / response to UV-A / tongue development / PLCG1 events in ERBB2 signaling / midgut development / hydrogen peroxide metabolic process / regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / ERBB2-EGFR signaling pathway / PTK6 promotes HIF1A stabilization / digestive tract morphogenesis / morphogenesis of an epithelial fold / ERBB2 Activates PTK6 Signaling / intracellular vesicle / Signaling by EGFR / transmembrane receptor protein tyrosine kinase activator activity / negative regulation of epidermal growth factor receptor signaling pathway / response to cobalamin / Signaling by ERBB4 / protein tyrosine kinase activator activity / eyelid development in camera-type eye / protein insertion into membrane / cerebral cortex cell migration / ERBB2 Regulates Cell Motility / regulation of JNK cascade / Respiratory syncytial virus (RSV) attachment and entry / PI3K events in ERBB2 signaling / positive regulation of cyclin-dependent protein serine/threonine kinase activity / negative regulation of mitotic cell cycle / MAP kinase kinase kinase activity / hair follicle development / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / embryonic placenta development / positive regulation of bone resorption / GAB1 signalosome / positive regulation of G1/S transition of mitotic cell cycle / salivary gland morphogenesis / peptidyl-tyrosine autophosphorylation / positive regulation of phosphorylation / regulation of peptidyl-tyrosine phosphorylation / positive regulation of glial cell proliferation / Signaling by ERBB2 / positive regulation of vasoconstriction / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / cellular response to epidermal growth factor stimulus / cellular response to cadmium ion / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / GRB2 events in ERBB2 signaling / transmembrane receptor protein tyrosine kinase activity / positive regulation of DNA repair / SHC1 events in ERBB2 signaling / cellular response to dexamethasone stimulus / ossification / regulation of ERK1 and ERK2 cascade / positive regulation of synaptic transmission, glutamatergic / basal plasma membrane / neuron projection morphogenesis / neurogenesis / positive regulation of epithelial cell proliferation / positive regulation of superoxide anion generation / positive regulation of DNA replication / epithelial cell proliferation / Signal transduction by L1 / cellular response to estradiol stimulus / astrocyte activation / NOTCH3 Activation and Transmission of Signal to the Nucleus / liver regeneration / positive regulation of protein localization to plasma membrane / Signaling by ERBB2 TMD/JMD mutants / cellular response to amino acid stimulus / positive regulation of smooth muscle cell proliferation / EGFR downregulation / lung development / positive regulation of MAP kinase activity / Constitutive Signaling by EGFRvIII / clathrin-coated endocytic vesicle membrane / Signaling by ERBB2 ECD mutants / epidermal growth factor receptor signaling pathway / Signaling by ERBB2 KD Mutants / negative regulation of protein catabolic process / receptor protein-tyrosine kinase / kinase binding / positive regulation of miRNA transcription / Downregulation of ERBB2 signaling / cell-cell adhesion / ruffle membrane / HCMV Early Events
Similarity search - Function
24 nucleotide stem-loop, u2 snrnp hairpin iv. U2 a'; Chain A / Receptor L-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 / : / 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 ...24 nucleotide stem-loop, u2 snrnp hairpin iv. U2 a'; Chain A / Receptor L-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 / : / 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 / Immunoglobulins / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / 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: 3.054 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. / 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 2.2Nov 20, 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 EgA1
C: Cetuximab light chain
D: Cetuximab heavy chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)133,0559
Polymers131,5434
Non-polymers1,5125
Water21612
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)66.207, 96.288, 128.097
Angle α, β, γ (deg.)90.00, 100.68, 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 EgA1


Mass: 15546.174 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, 13 molecules A

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


Mass: 69198.711 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.: 12 / Source method: isolated from a natural source / Formula: H2O

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Sugars , 2 types, 5 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.: 3
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: 3.08 Å3/Da / Density % sol: 60.05 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 17.5% PEG3350, 1.5 M sodium chloride, 5% glycerol, 0.1 M MES, pH 6.5, VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: CHESS / Beamline: F1 / Wavelength: 0.918 Å
DetectorType: ADSC QUANTUM 270 / Detector: CCD / Date: Dec 18, 2008
RadiationMonochromator: Single-crystal Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.918 Å / Relative weight: 1
ReflectionResolution: 3.05→50 Å / Num. all: 29807 / Num. obs: 29807 / % possible obs: 98.8 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 2.3 % / Rmerge(I) obs: 0.099 / Χ2: 1.486 / Net I/σ(I): 10.2
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2Diffraction-ID% possible all
3.05-3.12.30.46314951.404199.6
3.1-3.162.30.40515221.266199.7
3.16-3.222.30.33814581.334199.7
3.22-3.292.40.29215071.283199.5
3.29-3.362.30.2514811.277199.7
3.36-3.432.30.22315121.421199.3
3.43-3.522.30.18314791.352199.5
3.52-3.622.30.1714851.436199.5
3.62-3.722.30.14215031.499199.5
3.72-3.842.40.11514871.403199.3
3.84-3.982.30.10314891.397199.2
3.98-4.142.40.08915171.522199.2
4.14-4.332.30.07614751.704199.1
4.33-4.562.30.06114971.697199.1
4.56-4.842.40.05414821.738198.9
4.84-5.212.30.04914831.633198.7
5.21-5.742.30.05314961.612198.3
5.74-6.572.30.05114991.599198.4
6.57-8.272.30.0414981.655197.6
8.27-502.20.0314421.485192.3

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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
ADSCQuantumdata collection
HKL-2000data reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1YY9 AND 4KRN

1yy9

4krn


Resolution: 3.054→38.193 Å / Occupancy max: 1 / Occupancy min: 1 / FOM work R set: 0.7715 / SU ML: 0.44 / σ(F): 1.34 / Phase error: 29.7 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2795 1507 5.06 %RANDOM
Rwork0.2205 ---
obs0.2235 29786 98.58 %-
all-29786 --
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 216.53 Å2 / Biso mean: 61.9335 Å2 / Biso min: 9.61 Å2
Refinement stepCycle: LAST / Resolution: 3.054→38.193 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7839 0 98 12 7949
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0058141
X-RAY DIFFRACTIONf_angle_d0.89711168
X-RAY DIFFRACTIONf_chiral_restr0.0331310
X-RAY DIFFRACTIONf_plane_restr0.0041447
X-RAY DIFFRACTIONf_dihedral_angle_d13.992705
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 11

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
3.054-3.15210.39031320.31312554268697
3.1521-3.26470.32761270.285625562683100
3.2647-3.39530.34751340.266425802714100
3.3953-3.54970.30631250.23672607273299
3.5497-3.73670.2881330.22072581271499
3.7367-3.97060.30361400.21222566270699
3.9706-4.27680.24951480.19852586273499
4.2768-4.70650.23091300.17262591272199
4.7065-5.38590.23751430.18172556269999
5.3859-6.77950.26171520.22452573272598
6.7795-38.19630.27951430.22312529267295

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