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Yorodumi- EMDB-23918: Structure of the HER2/HER3/NRG1b Heterodimer Extracellular Domain... -
+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-23918 | ||||||||||||
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Title | Structure of the HER2/HER3/NRG1b Heterodimer Extracellular Domain bound to Trastuzumab Fab | ||||||||||||
Map data | Main map from non-uniform refinement in cryosparc, filtered to 3.45A in resolution and sharpened with a B-factor of 100.3 | ||||||||||||
Sample |
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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 / positive regulation of calcineurin-NFAT signaling cascade / peripheral nervous system development / regulation of microtubule-based process / ErbB-3 class receptor binding / negative regulation of cell adhesion / negative regulation of motor neuron apoptotic process / semaphorin receptor complex / Sema4D induced cell migration and growth-cone collapse / motor neuron axon guidance / neurotransmitter receptor localization to postsynaptic specialization membrane / motor neuron apoptotic process / PLCG1 events in ERBB2 signaling / neuromuscular junction development / ERBB2-EGFR signaling pathway / ERBB2 Activates PTK6 Signaling / positive regulation of Rho protein signal transduction / detection of maltose stimulus / 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 / positive regulation of transcription by RNA polymerase I / maltose transport complex / ERBB2-ERBB3 signaling pathway / protein tyrosine kinase activator activity / Signaling by ERBB4 / oligodendrocyte differentiation / growth factor binding / carbohydrate transport / ERBB2 Regulates Cell Motility / semaphorin-plexin signaling pathway / PI3K events in ERBB2 signaling / carbohydrate transmembrane transporter activity / positive regulation of cell adhesion / maltose binding / lateral plasma membrane / maltose transport / maltodextrin transmembrane transport / positive regulation of protein targeting to membrane / regulation of angiogenesis / coreceptor activity / Schwann cell development / negative regulation of signal transduction / ATP-binding cassette (ABC) transporter complex, substrate-binding subunit-containing / extrinsic apoptotic signaling pathway in absence of ligand / Signaling by ERBB2 / cellular response to epidermal growth factor stimulus / cell surface receptor protein tyrosine kinase signaling pathway / myelination / Downregulation of ERBB2:ERBB3 signaling / GRB2 events in ERBB2 signaling / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / transmembrane receptor protein tyrosine kinase activity / ATP-binding cassette (ABC) transporter complex / SHC1 events in ERBB2 signaling / Constitutive Signaling by Overexpressed ERBB2 / phosphatidylinositol 3-kinase/protein kinase B signal transduction / basal plasma membrane / neurogenesis / regulation of ERK1 and ERK2 cascade / cell chemotaxis / positive regulation of translation / positive regulation of epithelial cell proliferation / Signaling by ERBB2 TMD/JMD mutants / positive regulation of MAP kinase activity / wound healing / Signaling by ERBB2 ECD mutants / neuromuscular junction / neuron differentiation / Signaling by ERBB2 KD Mutants / receptor protein-tyrosine kinase / receptor tyrosine kinase binding / cellular response to growth factor stimulus / Downregulation of ERBB2 signaling / ruffle membrane / peptidyl-tyrosine phosphorylation / transmembrane signaling receptor activity / Constitutive Signaling by Aberrant PI3K in Cancer / PIP3 activates AKT signaling / myelin sheath Similarity search - Function | ||||||||||||
Biological species | Homo sapiens (human) / Escherichia coli (E. coli) | ||||||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.45 Å | ||||||||||||
Authors | Diwanji D / Trenker R / Verba KA / Jura N | ||||||||||||
Funding support | United States, Germany, 3 items
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Citation | Journal: 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 |
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-Structure visualization
Movie |
Movie viewer |
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Structure viewer | EM map: SurfViewMolmilJmol/JSmol |
Supplemental images |
-Downloads & links
-EMDB archive
Map data | emd_23918.map.gz | 307 MB | EMDB map data format | |
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Header (meta data) | emd-23918-v30.xml emd-23918.xml | 26.3 KB 26.3 KB | Display Display | EMDB header |
FSC (resolution estimation) | emd_23918_fsc.xml | 15.4 KB | Display | FSC data file |
Images | emd_23918.png | 176.4 KB | ||
Masks | emd_23918_msk_1.map | 325 MB | Mask map | |
Others | emd_23918_half_map_1.map.gz emd_23918_half_map_2.map.gz | 301.4 MB 301.4 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-23918 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-23918 | HTTPS FTP |
-Validation report
Summary document | emd_23918_validation.pdf.gz | 189.1 KB | Display | EMDB validaton report |
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Full document | emd_23918_full_validation.pdf.gz | 188.7 KB | Display | |
Data in XML | emd_23918_validation.xml.gz | 503 B | Display | |
Data in CIF | emd_23918_validation.cif.gz | 373 B | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-23918 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-23918 | HTTPS FTP |
-Related structure data
Related structure data | 7mn8MC 7mn5C 7mn6C M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_23918.map.gz / Format: CCP4 / Size: 325 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Annotation | Main map from non-uniform refinement in cryosparc, filtered to 3.45A in resolution and sharpened with a B-factor of 100.3 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 0.834 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
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-Supplemental data
-Mask #1
File | emd_23918_msk_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: EM Half-map A
File | emd_23918_half_map_1.map | ||||||||||||
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Annotation | EM Half-map A | ||||||||||||
Projections & Slices |
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Density Histograms |
-Half map: EM Half-map B
File | emd_23918_half_map_2.map | ||||||||||||
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Annotation | EM Half-map B | ||||||||||||
Projections & Slices |
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Density Histograms |
-Sample components
+Entire : NRG1b-bound HER2/HER3 Heterodimer bound to the Trastuzumab Fab in...
+Supramolecule #1: NRG1b-bound HER2/HER3 Heterodimer bound to the Trastuzumab Fab in...
+Supramolecule #2: Trastuzumab (Herceptin) Fab
+Supramolecule #3: Neuregulin-1b isoform 6
+Supramolecule #4: HER3
+Supramolecule #5: HER2-S310F-MBP Fusion
+Macromolecule #1: Receptor tyrosine-protein kinase erbB-3
+Macromolecule #2: Isoform 6 of Pro-neuregulin-1, membrane-bound isoform
+Macromolecule #3: Receptor tyrosine-protein kinase erbB-2,Maltose/maltodextrin-bind...
+Macromolecule #4: Trastuzumab Fab Light Chain
+Macromolecule #5: Trastuzumab Fab Heavy Chain
+Macromolecule #8: 2-acetamido-2-deoxy-beta-D-glucopyranose
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Buffer | pH: 7.4 |
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Vitrification | Cryogen name: ETHANE |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Specialist optics | Energy filter - Slit width: 20 eV |
Image recording | Film or detector model: GATAN K3 (6k x 4k) / Average electron dose: 66.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD |
Sample stage | Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |