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- EMDB-20055: Cryo-EM structure of Her2 extracellular domain-Trastuzumab Fab-Pe... -
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Open data
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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 | |||||||||
![]() | Sharpened map with phenix.auto_sharpen | |||||||||
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Function / homology | ![]() 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 / regulation of microtubule-based process / CD22 mediated BCR regulation / ErbB-3 class receptor binding / semaphorin receptor complex / Sema4D induced cell migration and growth-cone collapse / IgG immunoglobulin complex / motor neuron axon guidance / neurotransmitter receptor localization to postsynaptic specialization membrane / Fc epsilon receptor (FCERI) signaling / PLCG1 events in ERBB2 signaling / Classical antibody-mediated complement activation / neuromuscular junction development / ERBB2-EGFR signaling pathway / ERBB2 Activates PTK6 Signaling / positive regulation of Rho protein signal transduction / 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 / positive regulation of transcription by RNA polymerase I / ERBB2-ERBB3 signaling pathway / oligodendrocyte differentiation / ERBB2 Regulates Cell Motility / semaphorin-plexin signaling pathway / PI3K events in ERBB2 signaling / positive regulation of cell adhesion / FCGR activation / immunoglobulin mediated immune response / positive regulation of protein targeting to membrane / Role of phospholipids in phagocytosis / Role of LAT2/NTAL/LAB on calcium mobilization / regulation of angiogenesis / Scavenging of heme from plasma / coreceptor activity / Schwann cell development / Signaling by ERBB2 / immunoglobulin complex, circulating / cellular response to epidermal growth factor stimulus / immunoglobulin receptor binding / cell surface receptor protein tyrosine kinase signaling pathway / myelination / GRB2 events in ERBB2 signaling / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / Downregulation of ERBB2:ERBB3 signaling / transmembrane receptor protein tyrosine kinase activity / SHC1 events in ERBB2 signaling / Constitutive Signaling by Overexpressed ERBB2 / FCERI mediated Ca+2 mobilization / FCGR3A-mediated IL10 synthesis / phosphatidylinositol 3-kinase/protein kinase B signal transduction / neurogenesis / regulation of ERK1 and ERK2 cascade / basal plasma membrane / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / complement activation, classical pathway / Regulation of Complement cascade / positive regulation of epithelial cell proliferation / positive regulation of translation / Cell surface interactions at the vascular wall / FCERI mediated MAPK activation / FCGR3A-mediated phagocytosis / antigen binding / Signaling by ERBB2 TMD/JMD mutants / B cell receptor signaling pathway / 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 / Regulation of actin dynamics for phagocytic cup formation / cellular response to growth factor stimulus / Downregulation of ERBB2 signaling / ruffle membrane / FCERI mediated NF-kB activation / peptidyl-tyrosine phosphorylation / transmembrane signaling receptor activity / Constitutive Signaling by Aberrant PI3K in Cancer / Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell / PIP3 activates AKT signaling Similarity search - Function | |||||||||
Biological species | ![]() | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 4.36 Å | |||||||||
![]() | Hao Y / Yu X / Bai Y / Huang X | |||||||||
![]() | ![]() 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
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Structure viewer | EM map: ![]() ![]() ![]() |
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 31.9 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 19 KB 19 KB | Display Display | ![]() |
Images | ![]() | 145.4 KB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Validation report
Summary document | ![]() | 475.5 KB | Display | ![]() |
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Full document | ![]() | 475.1 KB | Display | |
Data in XML | ![]() | 6 KB | Display | |
Data in CIF | ![]() | 6.8 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 6ogeMC M: atomic model generated by this map C: citing same article ( |
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Similar structure data |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
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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
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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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![]() | single particle reconstruction |
Aggregation state | particle |
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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 |
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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: ![]() |
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 |
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Image processing
-Atomic model buiding 1
Refinement | Space: REAL / Protocol: FLEXIBLE FIT |
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Output model | ![]() PDB-6oge: |