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Yorodumi- EMDB-20055: Cryo-EM structure of Her2 extracellular domain-Trastuzumab Fab-Pe... -
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-Basic information
Entry | Database: EMDB / ID: EMD-20055 | |||||||||
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Title | Cryo-EM structure of Her2 extracellular domain-Trastuzumab Fab-Pertuzumab Fab complex | |||||||||
Map data | Sharpened map with phenix.auto_sharpen | |||||||||
Sample |
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Function / homology | Function and homology information negative regulation of immature T cell proliferation in thymus / ERBB3:ERBB2 complex / ERBB2-ERBB4 signaling pathway / IgD immunoglobulin complex / GRB7 events in ERBB2 signaling / immature T cell proliferation in thymus / RNA polymerase I core binding / IgM immunoglobulin complex / IgA immunoglobulin complex / IgE immunoglobulin complex ...negative regulation of immature T cell proliferation in thymus / ERBB3:ERBB2 complex / ERBB2-ERBB4 signaling pathway / IgD immunoglobulin complex / GRB7 events in ERBB2 signaling / immature T cell proliferation in thymus / RNA polymerase I core binding / IgM immunoglobulin complex / IgA immunoglobulin complex / IgE immunoglobulin complex / semaphorin receptor complex / regulation of microtubule-based process / ErbB-3 class receptor binding / CD22 mediated BCR regulation / Sema4D induced cell migration and growth-cone collapse / motor neuron axon guidance / immunoglobulin complex / neurotransmitter receptor localization to postsynaptic specialization membrane / Fc epsilon receptor (FCERI) signaling / PLCG1 events in ERBB2 signaling / positive regulation of Rho protein signal transduction / ERBB2-ERBB3 signaling pathway / Classical antibody-mediated complement activation / enzyme-linked receptor protein signaling pathway / ERBB2-EGFR signaling pathway / neuromuscular junction development / ERBB2 Activates PTK6 Signaling / Initial triggering of complement / 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 / positive regulation of transcription by RNA polymerase I / IgG immunoglobulin complex / oligodendrocyte differentiation / ERBB2 Regulates Cell Motility / semaphorin-plexin signaling pathway / immunoglobulin mediated immune response / PI3K events in ERBB2 signaling / positive regulation of protein targeting to membrane / FCGR activation / positive regulation of cell adhesion / Role of phospholipids in phagocytosis / Schwann cell development / Role of LAT2/NTAL/LAB on calcium mobilization / regulation of angiogenesis / Scavenging of heme from plasma / coreceptor activity / Signaling by ERBB2 / myelination / cellular response to epidermal growth factor stimulus / antigen binding / Downregulation of ERBB2:ERBB3 signaling / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / GRB2 events in ERBB2 signaling / neurogenesis / transmembrane receptor protein tyrosine kinase activity / SHC1 events in ERBB2 signaling / FCERI mediated Ca+2 mobilization / Constitutive Signaling by Overexpressed ERBB2 / basal plasma membrane / FCGR3A-mediated IL10 synthesis / regulation of ERK1 and ERK2 cascade / phosphatidylinositol 3-kinase/protein kinase B signal transduction / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / positive regulation of epithelial cell proliferation / Regulation of Complement cascade / positive regulation of translation / Cell surface interactions at the vascular wall / FCGR3A-mediated phagocytosis / FCERI mediated MAPK activation / Signaling by ERBB2 TMD/JMD mutants / B cell receptor signaling pathway / neuromuscular junction / wound healing / positive regulation of MAP kinase activity / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / neuron differentiation / receptor protein-tyrosine kinase / Regulation of actin dynamics for phagocytic cup formation / Downregulation of ERBB2 signaling / FCERI mediated NF-kB activation / receptor tyrosine kinase binding / cellular response to growth factor stimulus / ruffle membrane / peptidyl-tyrosine phosphorylation / cell surface receptor protein tyrosine kinase signaling pathway / Constitutive Signaling by Aberrant PI3K in Cancer / Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell / transmembrane signaling receptor activity / presynaptic membrane / PIP3 activates AKT signaling / myelin sheath Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 4.36 Å | |||||||||
Authors | Hao Y / Yu X / Bai Y / Huang X | |||||||||
Citation | Journal: PLoS One / Year: 2019 Title: Cryo-EM Structure of HER2-trastuzumab-pertuzumab complex. Authors: Yue Hao / Xinchao Yu / Yonghong Bai / Helen J McBride / Xin Huang / Abstract: Trastuzumab and pertuzumab are monoclonal antibodies that bind to distinct subdomains of the extracellular domain of human epidermal growth factor receptor 2 (HER2). Adding these monoclonal ...Trastuzumab and pertuzumab are monoclonal antibodies that bind to distinct subdomains of the extracellular domain of human epidermal growth factor receptor 2 (HER2). Adding these monoclonal antibodies to the treatment regimen of HER2-positive breast cancer has changed the paradigm for treatment in that form of cancer. Synergistic activity has been observed with the combination of these two antibodies leading to hypotheses regarding the mechanism(s) and to the development of bispecific antibodies to maximize the clinical effect further. Although the individual crystal structures of HER2-trastuzumab and HER2-pertuzumab revealed the distinct binding sites and provided the structural basis for their anti-tumor activities, detailed structural information on the HER2-trastuzumab-pertuzumab complex has been elusive. Here we present the cryo-EM structure of HER2-trastuzumab-pertuzumab at 4.36 Å resolution. Comparison with the binary complexes reveals no cooperative interaction between trastuzumab and pertuzumab, and provides key insights into the design of novel, high-avidity bispecific molecules with potentially greater clinical efficacy. | |||||||||
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_20055.map.gz | 31.9 MB | EMDB map data format | |
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Header (meta data) | emd-20055-v30.xml emd-20055.xml | 19 KB 19 KB | Display Display | EMDB header |
Images | emd_20055.png | 145.4 KB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-20055 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-20055 | HTTPS FTP |
-Related structure data
Related structure data | 6ogeMC 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_20055.map.gz / Format: CCP4 / Size: 34.3 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Annotation | Sharpened map with phenix.auto_sharpen | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 1.059 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
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-Supplemental data
-Sample components
+Entire : Her2 extracellular domain-Trastuzumab Fab-Pertuzumab Fab complex
+Supramolecule #1: Her2 extracellular domain-Trastuzumab Fab-Pertuzumab Fab complex
+Supramolecule #2: Human HER2 extracellular domain
+Supramolecule #3: Pertuzumab Fab
+Supramolecule #4: Trastuzumab Fab
+Macromolecule #1: Receptor tyrosine-protein kinase erbB-2
+Macromolecule #2: Pertuzumab FAB LIGHT CHAIN
+Macromolecule #3: Pertuzumab FAB HEAVY CHAIN
+Macromolecule #4: Trastuzumab FAB LIGHT CHAIN
+Macromolecule #5: Trastuzumab FAB HEAVY CHAIN
+Macromolecule #7: 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
Concentration | 2.4 mg/mL | |||||||||
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Buffer | pH: 7.5 Component:
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Grid | Model: Quantifoil R1.2/1.3 / Mesh: 300 | |||||||||
Vitrification | Cryogen name: ETHANE / Chamber humidity: 100 % / Instrument: FEI VITROBOT MARK IV |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Cs: 2.7 mm / Nominal defocus max: -1.5 µm / Nominal defocus min: -3.5 µm / Nominal magnification: 130000 |
Image recording | Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: SUPER-RESOLUTION / Average exposure time: 6.0 sec. / Average electron dose: 45.0 e/Å2 |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
-Image processing
Particle selection | Number selected: 1032611 |
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CTF correction | Software - Name: CTFFIND |
Initial angle assignment | Type: RANDOM ASSIGNMENT / Software - Name: cisTEM |
Final angle assignment | Type: MAXIMUM LIKELIHOOD |
Final reconstruction | Applied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 4.36 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cisTEM / Number images used: 398409 |
-Atomic model buiding 1
Refinement | Space: REAL / Protocol: FLEXIBLE FIT |
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Output model | PDB-6oge: |