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- PDB-7mn8: Structure of the HER2/HER3/NRG1b Heterodimer Extracellular Domain... -

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Entry
Database: PDB / ID: 7mn8
TitleStructure of the HER2/HER3/NRG1b Heterodimer Extracellular Domain bound to Trastuzumab Fab
Components
  • (Receptor tyrosine-protein kinase erbB- ...) x 2
  • (Trastuzumab Fab ...) x 2
  • Isoform 6 of Pro-neuregulin-1, membrane-bound isoform
KeywordsSIGNALING PROTEIN/IMMUNE SYSTEM / Complex / Receptor Tyrosine Kinase / Herceptin / Trastuzumab / SIGNALING PROTEIN / SIGNALING PROTEIN-IMMUNE SYSTEM complex
Function / homology
Function and homology information


neuregulin binding / positive regulation of cardiac muscle tissue development / cranial nerve development / Schwann cell differentiation / neuregulin receptor activity / negative regulation of secretion / endocardial cushion development / negative regulation of immature T cell proliferation in thymus / ERBB3:ERBB2 complex / ERBB2-ERBB4 signaling pathway ...neuregulin binding / positive regulation of cardiac muscle tissue development / cranial nerve development / Schwann cell differentiation / neuregulin receptor activity / negative regulation of secretion / endocardial cushion development / negative regulation of immature T cell proliferation in thymus / ERBB3:ERBB2 complex / ERBB2-ERBB4 signaling pathway / GRB7 events in ERBB2 signaling / immature T cell proliferation in thymus / RNA polymerase I core binding / semaphorin receptor complex / positive regulation of calcineurin-NFAT signaling cascade / peripheral nervous system development / ErbB-3 class receptor binding / regulation of microtubule-based process / negative regulation of cell adhesion / negative regulation of motor neuron apoptotic process / Sema4D induced cell migration and growth-cone collapse / motor neuron axon guidance / motor neuron apoptotic process / neurotransmitter receptor localization to postsynaptic specialization membrane / PLCG1 events in ERBB2 signaling / ERBB2-EGFR signaling pathway / positive regulation of Rho protein signal transduction / ERBB2 Activates PTK6 Signaling / neuromuscular junction development / positive regulation of transcription by RNA polymerase I / 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 / detection of maltose stimulus / ERBB2-ERBB3 signaling pathway / protein tyrosine kinase activator activity / Signaling by ERBB4 / maltose transport complex / growth factor binding / oligodendrocyte differentiation / ERBB2 Regulates Cell Motility / maltose binding / carbohydrate transport / maltose transport / maltodextrin transmembrane transport / semaphorin-plexin signaling pathway / PI3K events in ERBB2 signaling / carbohydrate transmembrane transporter activity / lateral plasma membrane / positive regulation of protein targeting to membrane / ATP-binding cassette (ABC) transporter complex, substrate-binding subunit-containing / regulation of angiogenesis / negative regulation of signal transduction / coreceptor activity / Schwann cell development / cell surface receptor protein tyrosine kinase signaling pathway / extrinsic apoptotic signaling pathway in absence of ligand / Signaling by ERBB2 / cellular response to epidermal growth factor stimulus / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / myelination / GRB2 events in ERBB2 signaling / transmembrane receptor protein tyrosine kinase activity / phosphatidylinositol 3-kinase/protein kinase B signal transduction / regulation of ERK1 and ERK2 cascade / SHC1 events in ERBB2 signaling / positive regulation of cell adhesion / Downregulation of ERBB2:ERBB3 signaling / Constitutive Signaling by Overexpressed ERBB2 / neurogenesis / ATP-binding cassette (ABC) transporter complex / positive regulation of epithelial cell proliferation / basal plasma membrane / cell chemotaxis / positive regulation of translation / Signaling by ERBB2 TMD/JMD mutants / positive regulation of MAP kinase activity / wound healing / Signaling by ERBB2 ECD mutants / neuromuscular junction / Signaling by ERBB2 KD Mutants / receptor protein-tyrosine kinase / neuron differentiation / cellular response to growth factor stimulus / receptor tyrosine kinase binding / Downregulation of ERBB2 signaling / peptidyl-tyrosine phosphorylation / ruffle membrane / Constitutive Signaling by Aberrant PI3K in Cancer / transmembrane signaling receptor activity / PIP3 activates AKT signaling / myelin sheath
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 / Maltose/Cyclodextrin ABC transporter, substrate-binding protein / Furin-like repeat / Furin-like repeats / Solute-binding family 1, conserved site / Bacterial extracellular solute-binding proteins, family 1 signature. / Bacterial extracellular solute-binding protein / Bacterial extracellular solute-binding protein / 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
Receptor tyrosine-protein kinase erbB-2 / Maltose/maltodextrin-binding periplasmic protein / Receptor tyrosine-protein kinase erbB-3 / Isoform 6 of Pro-neuregulin-1, membrane-bound isoform
Similarity search - Component
Biological speciesHomo sapiens (human)
Escherichia coli (E. coli)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.45 Å
AuthorsDiwanji, D. / Trenker, R. / Verba, K.A. / Jura, N.
Funding support United States, Germany, 3items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM139635 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)1F30CA247147 United States
German Research Foundation (DFG)TR 1668/1-1 Germany
CitationJournal: Nature / Year: 2021
Title: Structures of the HER2-HER3-NRG1β complex reveal a dynamic dimer interface.
Authors: Devan Diwanji / Raphael Trenker / Tarjani M Thaker / Feng Wang / David A Agard / Kliment A Verba / Natalia Jura /
Abstract: Human epidermal growth factor receptor 2 (HER2) and HER3 form a potent pro-oncogenic heterocomplex upon binding of growth factor neuregulin-1β (NRG1β). The mechanism by which HER2 and HER3 interact ...Human epidermal growth factor receptor 2 (HER2) and HER3 form a potent pro-oncogenic heterocomplex upon binding of growth factor neuregulin-1β (NRG1β). The mechanism by which HER2 and HER3 interact remains unknown in the absence of any structures of the complex. Here we isolated the NRG1β-bound near full-length HER2-HER3 dimer and, using cryo-electron microscopy, reconstructed the extracellulardomain module, revealing unexpected dynamics at the HER2-HER3 dimerization interface. We show that the dimerization arm of NRG1β-bound HER3 is unresolved because the apo HER2 monomer does not undergo a ligand-induced conformational change needed to establish a HER3 dimerization arm-binding pocket. In a structure of the oncogenic extracellular domain mutant HER2(S310F), we observe a compensatory interaction with the HER3 dimerization arm that stabilizes the dimerization interface. Both HER2-HER3 and HER2(S310F)-HER3 retain the capacity to bind to the HER2-directed therapeutic antibody trastuzumab, but the mutant complex does not bind to pertuzumab. Our structure of the HER2(S310F)-HER3-NRG1β-trastuzumab Fab complex reveals that the receptor dimer undergoes a conformational change to accommodate trastuzumab. Thus, similar to oncogenic mutations, therapeutic agents exploit the intrinsic dynamics of the HER2-HER3 heterodimer. The unique features of a singly liganded HER2-HER3 heterodimer underscore the allosteric sensing of ligand occupancy by the dimerization interface and explain why extracellular domains of HER2 do not homo-associate via a canonical active dimer interface.
History
DepositionApr 30, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 10, 2021Provider: repository / Type: Initial release
Revision 1.1Dec 1, 2021Group: Database references / Source and taxonomy / Category: citation / citation_author / entity_src_gen
Item: _citation.pdbx_database_id_PubMed / _citation.title ..._citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID / _entity_src_gen.pdbx_gene_src_scientific_name
Revision 1.2Dec 22, 2021Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.3Oct 23, 2024Group: Data collection / Refinement description / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / em_3d_fitting_list / em_admin / pdbx_entry_details / pdbx_initial_refinement_model / pdbx_modification_feature
Item: _em_3d_fitting_list.accession_code / _em_3d_fitting_list.initial_refinement_model_id ..._em_3d_fitting_list.accession_code / _em_3d_fitting_list.initial_refinement_model_id / _em_3d_fitting_list.source_name / _em_3d_fitting_list.type / _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Structure visualization

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Assembly

Deposited unit
A: Receptor tyrosine-protein kinase erbB-3
H: Isoform 6 of Pro-neuregulin-1, membrane-bound isoform
B: Receptor tyrosine-protein kinase erbB-2,Maltose/maltodextrin-binding periplasmic protein
C: Trastuzumab Fab Light Chain
D: Trastuzumab Fab Heavy Chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)340,88513
Polymers338,1825
Non-polymers2,7048
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: immunoprecipitation
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Receptor tyrosine-protein kinase erbB- ... , 2 types, 2 molecules AB

#1: Protein Receptor tyrosine-protein kinase erbB-3 / Proto-oncogene-like protein c-ErbB-3 / Tyrosine kinase-type cell surface receptor HER3


Mass: 117852.719 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ERBB3, HER3 / Production host: Homo sapiens (human)
References: UniProt: P21860, receptor protein-tyrosine kinase
#3: Protein Receptor tyrosine-protein kinase erbB-2,Maltose/maltodextrin-binding periplasmic protein / Tyrosine kinase-type cell surface receptor HER2 / MBP


Mass: 160556.562 Da / Num. of mol.: 1 / Mutation: S310F
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human), (gene. exp.) Escherichia coli (E. coli)
Gene: ERBB2, HER2, MLN19, NEU, NGL, malE, b4034, JW3994 / Strain: K12 / Production host: Homo sapiens (human)
References: UniProt: P04626, UniProt: P0AEX9, receptor protein-tyrosine kinase

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Protein , 1 types, 1 molecules H

#2: Protein Isoform 6 of Pro-neuregulin-1, membrane-bound isoform / Pro-NRG1


Mass: 9748.859 Da / Num. of mol.: 1 / Fragment: EGF-like Domain
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NRG1, GGF, HGL, HRGA, NDF, SMDF / Production host: Escherichia coli (E. coli) / References: UniProt: Q02297-6

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Antibody , 2 types, 2 molecules CD

#4: Antibody Trastuzumab Fab Light Chain


Mass: 24664.189 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#5: Antibody Trastuzumab Fab Heavy Chain


Mass: 25359.266 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)

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Sugars , 3 types, 8 molecules

#6: 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
#7: 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
#8: 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: 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 ligand of interestN
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

Component
IDNameTypeEntity IDParent-IDSource
1NRG1b-bound HER2/HER3 Heterodimer bound to the Trastuzumab Fab in the context of near full-length receptorsCOMPLEX#1-#50MULTIPLE SOURCES
2Trastuzumab (Herceptin) FabCOMPLEX#4-#51RECOMBINANT
3Neuregulin-1b isoform 6COMPLEX#21RECOMBINANT
4HER3COMPLEX#11RECOMBINANT
5HER2-S310F-MBP FusionCOMPLEX#31RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-IDStrain
22Homo sapiens (human)9606
33Homo sapiens (human)9606
44Homo sapiens (human)9606
55Homo sapiens (human)9606
65Escherichia coli (E. coli)83333K12
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
22Homo sapiens (human)9606
33Escherichia coli (E. coli)562
44Homo sapiens (human)9606
55Homo sapiens (human)9606
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Alignment procedure: ZEMLIN TABLEAU
Specimen holderSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 66 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)
EM imaging opticsEnergyfilter slit width: 20 eV

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Processing

EM software
IDNameVersionCategory
1cryoSPARC2.15.0particle selection
2SerialEM3.8.6image acquisition
3DigitalMicrograph3.31.2359.0image acquisition
5cryoSPARC2.15.0CTF correction
8UCSF ChimeraX1model fitting
10cryoSPARC2.15.0initial Euler assignment
11cryoSPARC2.15.0final Euler assignment
12RELION3classification
13cryoSPARC2.15.03D reconstruction
14Rosetta3.12model refinement
15ISOLDE1.0.1model refinement
16PHENIX1.18.2model refinement
17Coot0.9.1model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.45 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 243376 / Symmetry type: POINT
Atomic model building
IDPDB-ID 3D fitting-IDAccession codeInitial refinement model-IDSource nameType
13U7U

3u7u

13U7U1PDBexperimental model
21M6B

1m6b

11M6B2PDBexperimental model
31N8Z

1n8z

11N8Z3PDBexperimental model

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