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Yorodumi- 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 | |||||||||
Components |
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Keywords | transferase/immune system / Her2 extracellular domain / Trastuzumab / Pertuzumab / transferase-immune system complex | |||||||||
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 / CD22 mediated BCR regulation / ErbB-3 class receptor binding / Sema4D induced cell migration and growth-cone collapse / motor neuron axon guidance / neurotransmitter receptor localization to postsynaptic specialization membrane / Fc epsilon receptor (FCERI) signaling / PLCG1 events in ERBB2 signaling / positive regulation of Rho protein signal transduction / Classical antibody-mediated complement activation / 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 / enzyme-linked receptor protein signaling pathway / positive regulation of transcription by RNA polymerase I / ERBB2-ERBB3 signaling pathway / IgG immunoglobulin complex / oligodendrocyte differentiation / immunoglobulin complex / 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 / Role of LAT2/NTAL/LAB on calcium mobilization / regulation of angiogenesis / Scavenging of heme from plasma / coreceptor activity / Schwann cell development / Signaling by ERBB2 / cellular response to epidermal growth factor stimulus / antigen binding / myelination / Downregulation of ERBB2:ERBB3 signaling / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / GRB2 events in ERBB2 signaling / transmembrane receptor protein tyrosine kinase activity / neurogenesis / SHC1 events in ERBB2 signaling / Constitutive Signaling by Overexpressed ERBB2 / FCERI mediated Ca+2 mobilization / basal plasma membrane / FCGR3A-mediated IL10 synthesis / regulation of ERK1 and ERK2 cascade / positive regulation of translation / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of epithelial cell proliferation / Regulation of Complement cascade / 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 / positive regulation of MAP kinase activity / wound healing / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / receptor tyrosine kinase binding / receptor protein-tyrosine kinase / neuron differentiation / cellular response to growth factor stimulus / Regulation of actin dynamics for phagocytic cup formation / ruffle membrane / Downregulation of ERBB2 signaling / FCERI mediated NF-kB activation / 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 / PIP3 activates AKT signaling / presynaptic membrane / myelin sheath Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) | |||||||||
Method | ELECTRON MICROSCOPY / 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 | Molecule: MolmilJmol/JSmol |
-Downloads & links
-Download
PDBx/mmCIF format | 6oge.cif.gz | 264.4 KB | Display | PDBx/mmCIF format |
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PDB format | pdb6oge.ent.gz | 213.1 KB | Display | PDB format |
PDBx/mmJSON format | 6oge.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/og/6oge ftp://data.pdbj.org/pub/pdb/validation_reports/og/6oge | HTTPS FTP |
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-Related structure data
Related structure data | 20055MC M: map data used to model this data C: citing same article (ref.) |
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Similar structure data |
-Links
-Assembly
Deposited unit |
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1 |
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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.) Homo sapiens (human) / Gene: ERBB2, HER2, MLN19, NEU, NGL / Production host: Homo sapiens (human) 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.) Homo sapiens (human) / Gene: IGKC / Production host: Cricetulus griseus (Chinese hamster) / References: UniProt: P01834 |
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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.) Homo sapiens (human) / Production host: Cricetulus griseus (Chinese hamster) / References: UniProt: P0DOX5 |
#4: Antibody | Mass: 23466.031 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: IGKC / Production host: Cricetulus griseus (Chinese hamster) / References: UniProt: P01834 |
#5: Antibody | Mass: 23425.180 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: IGH@ / Production host: Cricetulus griseus (Chinese hamster) / References: UniProt: Q6GMX6 |
-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 / |
-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-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 % |
-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: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: BRIGHT FIELDBright-field microscopy / 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 |
-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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