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Yorodumi- EMDB-20055: Cryo-EM structure of Her2 extracellular domain-Trastuzumab Fab-Pe... -
+Open data
-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 / PLCG1 events in ERBB2 signaling / ERBB2-ERBB4 signaling pathway / IgD immunoglobulin complex / GRB7 events in ERBB2 signaling / immature T cell proliferation in thymus / RNA polymerase I core binding / ERBB2-EGFR signaling pathway / IgM immunoglobulin complex ...negative regulation of immature T cell proliferation in thymus / ERBB3:ERBB2 complex / PLCG1 events in ERBB2 signaling / ERBB2-ERBB4 signaling pathway / IgD immunoglobulin complex / GRB7 events in ERBB2 signaling / immature T cell proliferation in thymus / RNA polymerase I core binding / ERBB2-EGFR signaling pathway / IgM immunoglobulin complex / IgA immunoglobulin complex / IgE immunoglobulin complex / ERBB2 Activates PTK6 Signaling / semaphorin receptor complex / regulation of microtubule-based process / CD22 mediated BCR regulation / ErbB-3 class receptor binding / ERBB2 Regulates Cell Motility / Sema4D induced cell migration and growth-cone collapse / motor neuron axon guidance / IgG immunoglobulin complex / Fc epsilon receptor (FCERI) signaling / PI3K events in ERBB2 signaling / neurotransmitter receptor localization to postsynaptic specialization membrane / Classical antibody-mediated complement activation / positive regulation of Rho protein signal transduction / neuromuscular junction development / 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 / 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 / FCGR activation / immunoglobulin mediated immune response / positive regulation of protein targeting to membrane / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / GRB2 events in ERBB2 signaling / Role of phospholipids in phagocytosis / transmembrane receptor protein tyrosine kinase activity / Role of LAT2/NTAL/LAB on calcium mobilization / regulation of angiogenesis / neurogenesis / SHC1 events in ERBB2 signaling / Scavenging of heme from plasma / immunoglobulin complex, circulating / coreceptor activity / immunoglobulin receptor binding / 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 / FCERI mediated Ca+2 mobilization / FCGR3A-mediated IL10 synthesis / complement activation, classical pathway / Signaling by ERBB2 TMD/JMD mutants / positive regulation of MAP kinase activity / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / Signaling by ERBB2 ECD mutants / Regulation of Complement cascade / antigen binding / Signaling by ERBB2 KD Mutants / positive regulation of translation / receptor protein-tyrosine kinase / Cell surface interactions at the vascular wall / FCERI mediated MAPK activation / FCGR3A-mediated phagocytosis / Downregulation of ERBB2 signaling / B cell receptor signaling pathway / ruffle membrane / wound healing / neuromuscular junction / peptidyl-tyrosine phosphorylation / neuron differentiation / transmembrane signaling receptor activity / Regulation of actin dynamics for phagocytic cup formation / receptor tyrosine kinase binding / cellular response to growth factor stimulus / Constitutive Signaling by Aberrant PI3K in Cancer / FCERI mediated NF-kB activation / Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell / PIP3 activates AKT signaling 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 |
-Validation report
Summary document | emd_20055_validation.pdf.gz | 475.5 KB | Display | EMDB validaton report |
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Full document | emd_20055_full_validation.pdf.gz | 475.1 KB | Display | |
Data in XML | emd_20055_validation.xml.gz | 6 KB | Display | |
Data in CIF | emd_20055_validation.cif.gz | 6.8 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-20055 ftp://ftp.pdbj.org/pub/emdb/validation_reports/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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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 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: -1.5 µm / Nominal defocus min: -3.5 µm / Nominal magnification: 130000 |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
+Image processing
-Atomic model buiding 1
Refinement | Space: REAL / Protocol: FLEXIBLE FIT |
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Output model | PDB-6oge: |