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- PDB-6oge: Cryo-EM structure of Her2 extracellular domain-Trastuzumab Fab-Pe... -
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Basic information
Entry | Database: PDB / ID: 6oge | |||||||||
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Title | Cryo-EM structure of Her2 extracellular domain-Trastuzumab Fab-Pertuzumab Fab complex | |||||||||
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![]() | transferase/immune system / Her2 extracellular domain / Trastuzumab / Pertuzumab / transferase-immune system complex | |||||||||
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 / IgA immunoglobulin complex / IgM 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 / IgA immunoglobulin complex / IgM immunoglobulin complex / IgE immunoglobulin complex / semaphorin receptor complex / CD22 mediated BCR regulation / regulation of microtubule-based process / ErbB-3 class receptor binding / motor neuron axon guidance / Sema4D induced cell migration and growth-cone collapse / IgG immunoglobulin complex / Fc epsilon receptor (FCERI) signaling / Classical antibody-mediated complement activation / PLCG1 events in ERBB2 signaling / immunoglobulin complex / Initial triggering of complement / ERBB2-EGFR signaling pathway / neurotransmitter receptor localization to postsynaptic specialization membrane / ERBB2 Activates PTK6 Signaling / neuromuscular junction development / enzyme-linked receptor protein signaling pathway / ERBB2-ERBB3 signaling pathway / positive regulation of Rho protein signal transduction / 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 / ERBB2 Regulates Cell Motility / oligodendrocyte differentiation / semaphorin-plexin signaling pathway / immunoglobulin mediated immune response / PI3K events in ERBB2 signaling / FCGR activation / positive regulation of protein targeting to membrane / Role of LAT2/NTAL/LAB on calcium mobilization / regulation of angiogenesis / Role of phospholipids in phagocytosis / positive regulation of MAP kinase activity / regulation of ERK1 and ERK2 cascade / Schwann cell development / Scavenging of heme from plasma / antigen binding / coreceptor activity / Signaling by ERBB2 / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / transmembrane receptor protein tyrosine kinase activity / myelination / FCERI mediated Ca+2 mobilization / GRB2 events in ERBB2 signaling / positive regulation of cell adhesion / SHC1 events in ERBB2 signaling / Downregulation of ERBB2:ERBB3 signaling / FCGR3A-mediated IL10 synthesis / basal plasma membrane / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / cell surface receptor protein tyrosine kinase signaling pathway / Constitutive Signaling by Overexpressed ERBB2 / cellular response to epidermal growth factor stimulus / positive regulation of epithelial cell proliferation / Regulation of Complement cascade / positive regulation of translation / Cell surface interactions at the vascular wall / B cell receptor signaling pathway / FCGR3A-mediated phagocytosis / FCERI mediated MAPK activation / phosphatidylinositol 3-kinase/protein kinase B signal transduction / wound healing / peptidyl-tyrosine phosphorylation / Signaling by ERBB2 TMD/JMD mutants / receptor protein-tyrosine kinase / Signaling by ERBB2 ECD mutants / neuromuscular junction / Signaling by ERBB2 KD Mutants / receptor tyrosine kinase binding / Regulation of actin dynamics for phagocytic cup formation / cellular response to growth factor stimulus / FCERI mediated NF-kB activation / ruffle membrane / Downregulation of ERBB2 signaling / epidermal growth factor receptor signaling pathway / neuron differentiation / Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell / Constitutive Signaling by Aberrant PI3K in Cancer / transmembrane signaling receptor activity / PIP3 activates AKT signaling / myelin sheath / presynaptic membrane Similarity search - Function | |||||||||
Biological species | ![]() | |||||||||
Method | ELECTRON MICROSCOPY / 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 | Molecule: ![]() ![]() |
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Downloads & links
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PDBx/mmCIF format | ![]() | 271.6 KB | Display | ![]() |
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PDB format | ![]() | 213.2 KB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
Others | ![]() |
-Validation report
Summary document | ![]() | 1 MB | Display | ![]() |
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Full document | ![]() | 1 MB | Display | |
Data in XML | ![]() | 47.2 KB | Display | |
Data in CIF | ![]() | 71.3 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 20055MC M: map data used to model this data C: citing same article ( |
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Similar structure data |
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Links
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Assembly
Deposited unit | ![]()
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Components
-Protein , 1 types, 1 molecules A
#1: Protein | Mass: 68536.844 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() References: UniProt: P04626, receptor protein-tyrosine kinase |
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-Antibody , 4 types, 4 molecules BCDE
#2: Antibody | Mass: 23548.152 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() |
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#3: Antibody | Mass: 23674.486 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() |
#4: Antibody | Mass: 23466.031 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() |
#5: Antibody | Mass: 23425.180 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() |
-Sugars , 2 types, 6 molecules 
#6: 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 Source method: isolated from a genetically manipulated source |
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#7: Sugar | ChemComp-NAG / |
-Details
Has protein modification | Y |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
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Sample preparation
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Source (natural) |
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Source (recombinant) |
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Buffer solution | pH: 7.5 | ||||||||||||||||||||||||||||||
Buffer component |
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Specimen | Conc.: 2.4 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES | ||||||||||||||||||||||||||||||
Specimen support | Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3 | ||||||||||||||||||||||||||||||
Vitrification | Instrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % |
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Electron microscopy imaging
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: ![]() |
Electron lens | Mode: BRIGHT FIELD / Nominal magnification: 130000 X / Nominal defocus max: -1500 nm / Nominal defocus min: -3500 nm / Cs: 2.7 mm |
Image recording | Average exposure time: 6 sec. / Electron dose: 45 e/Å2 / Detector mode: SUPER-RESOLUTION / Film or detector model: GATAN K2 SUMMIT (4k x 4k) |
Image scans | Movie frames/image: 30 |
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Processing
Software | Name: PHENIX / Version: 1.13rc2_2986: / Classification: refinement | ||||||||||||||||||||||||
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EM software |
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
Particle selection | Num. of particles selected: 1032611 | ||||||||||||||||||||||||
Symmetry | Point symmetry: C1 (asymmetric) | ||||||||||||||||||||||||
3D reconstruction | Resolution: 4.36 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 398409 / Symmetry type: POINT | ||||||||||||||||||||||||
Atomic model building | Protocol: FLEXIBLE FIT / Space: REAL | ||||||||||||||||||||||||
Refine LS restraints |
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