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- PDB-6j71: HuA21-scFv in complex with the extracellular domain(ECD) of HER2 -

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Basic information

Entry
Database: PDB / ID: 6j71
TitleHuA21-scFv in complex with the extracellular domain(ECD) of HER2
Components
  • Receptor tyrosine-protein kinase erbB-2
  • anti-HER2 humanized antibody HuA21
KeywordsSIGNALING PROTEIN / Tyrosine-protein kinase / antibody / Transcription regulation
Function / homology
Function and homology information


negative regulation of immature T cell proliferation in thymus / ERBB3:ERBB2 complex / PLCG1 events in ERBB2 signaling / ERBB2-ERBB4 signaling pathway / GRB7 events in ERBB2 signaling / immature T cell proliferation in thymus / RNA polymerase I core binding / ERBB2-EGFR signaling pathway / ERBB2 Activates PTK6 Signaling / semaphorin receptor complex ...negative regulation of immature T cell proliferation in thymus / ERBB3:ERBB2 complex / PLCG1 events in ERBB2 signaling / ERBB2-ERBB4 signaling pathway / GRB7 events in ERBB2 signaling / immature T cell proliferation in thymus / RNA polymerase I core binding / ERBB2-EGFR signaling pathway / ERBB2 Activates PTK6 Signaling / semaphorin receptor complex / regulation of microtubule-based process / ErbB-3 class receptor binding / ERBB2 Regulates Cell Motility / Sema4D induced cell migration and growth-cone collapse / motor neuron axon guidance / PI3K events in ERBB2 signaling / neurotransmitter receptor localization to postsynaptic specialization membrane / positive regulation of Rho protein signal transduction / neuromuscular junction development / Drug-mediated inhibition of ERBB2 signaling / Resistance of ERBB2 KD mutants to trastuzumab / Resistance of ERBB2 KD mutants to sapitinib / Resistance of ERBB2 KD mutants to tesevatinib / Resistance of ERBB2 KD mutants to neratinib / Resistance of ERBB2 KD mutants to osimertinib / Resistance of ERBB2 KD mutants to afatinib / Resistance of ERBB2 KD mutants to AEE788 / Resistance of ERBB2 KD mutants to lapatinib / Drug resistance in ERBB2 TMD/JMD mutants / enzyme-linked receptor protein signaling pathway / ERBB2-ERBB3 signaling pathway / positive regulation of transcription by RNA polymerase I / oligodendrocyte differentiation / semaphorin-plexin signaling pathway / cellular response to epidermal growth factor stimulus / Signaling by ERBB2 / positive regulation of cell adhesion / positive regulation of protein targeting to membrane / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / GRB2 events in ERBB2 signaling / transmembrane receptor protein tyrosine kinase activity / regulation of angiogenesis / neurogenesis / SHC1 events in ERBB2 signaling / coreceptor activity / regulation of ERK1 and ERK2 cascade / Schwann cell development / basal plasma membrane / positive regulation of epithelial cell proliferation / cell surface receptor protein tyrosine kinase signaling pathway / myelination / phosphatidylinositol 3-kinase/protein kinase B signal transduction / Downregulation of ERBB2:ERBB3 signaling / Constitutive Signaling by Overexpressed ERBB2 / Signaling by ERBB2 TMD/JMD mutants / positive regulation of MAP kinase activity / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / positive regulation of translation / receptor protein-tyrosine kinase / Downregulation of ERBB2 signaling / ruffle membrane / wound healing / neuromuscular junction / peptidyl-tyrosine phosphorylation / neuron differentiation / transmembrane signaling receptor activity / receptor tyrosine kinase binding / cellular response to growth factor stimulus / Constitutive Signaling by Aberrant PI3K in Cancer / PIP3 activates AKT signaling / myelin sheath / presynaptic membrane / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / heart development / RAF/MAP kinase cascade / positive regulation of cell growth / basolateral plasma membrane / protein tyrosine kinase activity / receptor complex / positive regulation of MAPK cascade / cell surface receptor signaling pathway / endosome membrane / early endosome / intracellular signal transduction / positive regulation of protein phosphorylation / apical plasma membrane / protein heterodimerization activity / protein phosphorylation / signaling receptor binding / positive regulation of cell population proliferation / negative regulation of apoptotic process / perinuclear region of cytoplasm / signal transduction / nucleoplasm / ATP binding / identical protein binding / membrane / nucleus / plasma 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 / 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
Similarity search - Domain/homology
beta-D-mannopyranose / Receptor tyrosine-protein kinase erbB-2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.918 Å
AuthorsWang, Z. / Guo, G. / Cheng, B. / Zhu, Z. / Niu, L. / Zhang, H.
Funding support China, 6items
OrganizationGrant numberCountry
National Natural Science Foundation of ChinaU1632124 China
National Natural Science Foundation of China31270770 China
National Natural Science Foundation of China31621002 China
Ministry of Science and Technology (China)2017YFA0503600 China
Ministry of Science and Technology (China)2017YFA0504903 China
Ministry of Science and Technology (China)2012CB917200 China
CitationJournal: Acta Crystallogr D Struct Biol / Year: 2019
Title: Structural insight into a matured humanized monoclonal antibody HuA21 against HER2-overexpressing cancer cells.
Authors: Wang, Z. / Cheng, L. / Guo, G. / Cheng, B. / Hu, S. / Zhang, H. / Zhu, Z. / Niu, L.
History
DepositionJan 16, 2019Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Feb 27, 2019Provider: repository / Type: Initial release
Revision 1.1Jun 26, 2019Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.journal_abbrev / _citation.journal_id_CSD ..._citation.journal_abbrev / _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 / _citation_author.identifier_ORCID
Revision 1.2Nov 20, 2019Group: Source and taxonomy / Category: entity_src_gen
Item: _entity_src_gen.pdbx_gene_src_ncbi_taxonomy_id / _entity_src_gen.pdbx_gene_src_scientific_name
Revision 2.0Jul 29, 2020Group: Advisory / Atomic model ...Advisory / Atomic model / Data collection / Derived calculations / Structure summary
Category: atom_site / atom_site_anisotrop ...atom_site / atom_site_anisotrop / 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 / pdbx_validate_close_contact / struct_asym / struct_conn / 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_comp_id / _atom_site.auth_seq_id / _atom_site.label_asym_id / _atom_site.label_atom_id / _atom_site.label_comp_id / _atom_site.label_entity_id / _atom_site.occupancy / _atom_site.type_symbol / _atom_site_anisotrop.U[1][1] / _atom_site_anisotrop.U[1][2] / _atom_site_anisotrop.U[1][3] / _atom_site_anisotrop.U[2][2] / _atom_site_anisotrop.U[2][3] / _atom_site_anisotrop.U[3][3] / _atom_site_anisotrop.pdbx_auth_asym_id / _atom_site_anisotrop.pdbx_auth_atom_id / _atom_site_anisotrop.pdbx_auth_comp_id / _atom_site_anisotrop.pdbx_auth_seq_id / _atom_site_anisotrop.pdbx_label_asym_id / _atom_site_anisotrop.pdbx_label_atom_id / _atom_site_anisotrop.pdbx_label_comp_id / _atom_site_anisotrop.type_symbol / _chem_comp.name / _chem_comp.type / _entity.formula_weight / _entity.pdbx_description / _entity.pdbx_number_of_molecules / _entity.type / _pdbx_struct_assembly_gen.asym_id_list / _pdbx_validate_close_contact.auth_asym_id_2 / _pdbx_validate_close_contact.auth_seq_id_2 / _struct_conn.pdbx_role / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 2.1Nov 22, 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Receptor tyrosine-protein kinase erbB-2
B: anti-HER2 humanized antibody HuA21
hetero molecules


Theoretical massNumber of molelcules
Total (without water)95,8904
Polymers95,3262
Non-polymers5642
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration, Purified HuA21 scFv and HER2 ECD were mixed and incubated at 300K for 2 h. The complex was then purified by HiLoad 16/600 Superdex 200 column (GE Healthcare), and there was ...Evidence: gel filtration, Purified HuA21 scFv and HER2 ECD were mixed and incubated at 300K for 2 h. The complex was then purified by HiLoad 16/600 Superdex 200 column (GE Healthcare), and there was only one peak consisting of one HER2 and one HuA21 through SDS page.
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2420 Å2
ΔGint1 kcal/mol
Surface area40510 Å2
MethodPISA
Unit cell
Length a, b, c (Å)146.987, 78.073, 125.769
Angle α, β, γ (deg.)90.000, 107.470, 90.000
Int Tables number5
Space group name H-MC121

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Components

#1: Protein Receptor tyrosine-protein kinase erbB-2 / Metastatic lymph node gene 19 protein / MLN 19 / Proto-oncogene Neu / Proto-oncogene c-ErbB-2 / ...Metastatic lymph node gene 19 protein / MLN 19 / Proto-oncogene Neu / Proto-oncogene c-ErbB-2 / Tyrosine kinase-type cell surface receptor HER2 / p185erbB2


Mass: 68166.344 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ERBB2, HER2, MLN19, NEU, NGL / Production host: Cricetulus griseus (Chinese hamster)
References: UniProt: P04626, receptor protein-tyrosine kinase
#2: Antibody anti-HER2 humanized antibody HuA21


Mass: 27159.926 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Cricetulus griseus (Chinese hamster)
#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: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpb1-4DGlcpNAcb1-Glycam 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
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{}}}LINUCSPDB-CARE
#4: 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: isolated from a genetically manipulated source
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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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 3.45 Å3/Da / Density % sol: 64.3 %
Crystal growTemperature: 289 K / Method: vapor diffusion, hanging drop / pH: 6.5 / Details: 0.1 M MES monohydrate pH 6.5, 12% (w/v) PEG 20,000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL17U / Wavelength: 1.28211 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Nov 22, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.28211 Å / Relative weight: 1
ReflectionResolution: 2.918→50 Å / Num. obs: 28728 / % possible obs: 96.8 % / Redundancy: 6 % / Biso Wilson estimate: 67.45 Å2 / Rmerge(I) obs: 0.12 / Rpim(I) all: 0.053 / Rrim(I) all: 0.131 / Net I/σ(I): 13.89
Reflection shellResolution: 2.918→2.96 Å / Redundancy: 4.4 % / Rmerge(I) obs: 0.623 / Mean I/σ(I) obs: 2.06 / Num. unique obs: 1279 / % possible all: 84.5

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
PHENIX1.10.1_2155refinement
HKL-2000data reduction
SCALEPACKdata scaling
PHASERphasing
PDB_EXTRACT3.24data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3H3B, 3BE1

3h3b

3be1


Resolution: 2.918→40.024 Å / SU ML: 0.43 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 31.53
RfactorNum. reflection% reflection
Rfree0.2668 1399 4.87 %
Rwork0.208 --
obs0.2108 28700 96.27 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 212.98 Å2 / Biso mean: 82.1207 Å2 / Biso min: 20 Å2
Refinement stepCycle: final / Resolution: 2.918→40.024 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6565 0 36 0 6601
Biso mean--102.01 --
Num. residues----851
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0126788
X-RAY DIFFRACTIONf_angle_d1.5649261
X-RAY DIFFRACTIONf_chiral_restr0.0861022
X-RAY DIFFRACTIONf_plane_restr0.0071208
X-RAY DIFFRACTIONf_dihedral_angle_d23.5172550
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 10

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.9185-3.02280.39881170.31522311242882
3.0228-3.14380.34541470.28952707285496
3.1438-3.28680.33791460.26552724287097
3.2868-3.460.31261310.25742761289297
3.46-3.67660.32151440.23192718286297
3.6766-3.96020.32321440.20122783292798
3.9602-4.35830.24581380.16932803294199
4.3583-4.9880.21381300.15362788291899
4.988-6.28040.22281540.19682823297799
6.2804-40.02740.23151480.20862883303199
Refinement TLS params.Method: refined / Origin x: 630.7002 Å / Origin y: 148.255 Å / Origin z: 406.7093 Å
111213212223313233
T0.4716 Å2-0.0372 Å20.0212 Å2-0.359 Å20.0175 Å2--0.4764 Å2
L1.6886 °2-0.2272 °21.0487 °2-0.1661 °2-0.1251 °2--1.5059 °2
S-0.0917 Å °0.1968 Å °0.0581 Å °0.0083 Å °-0.0096 Å °-0.0754 Å °-0.0756 Å °0.1937 Å °0.0774 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allA22 - 639
2X-RAY DIFFRACTION1allA1001 - 1003
3X-RAY DIFFRACTION1allB5 - 258

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