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- EMDB-20055: Cryo-EM structure of Her2 extracellular domain-Trastuzumab Fab-Pe... -

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Basic information

Entry
Database: EMDB / ID: EMD-20055
TitleCryo-EM structure of Her2 extracellular domain-Trastuzumab Fab-Pertuzumab Fab complex
Map data
SampleHer2 extracellular domain-Trastuzumab Fab-Pertuzumab Fab complex:
Human HER2 extracellular domain / Pertuzumab Fab / Trastuzumab Fab / Receptor tyrosine-protein kinase erbB-2 / (Pertuzumab FAB ...) x 2 / (Trastuzumab FAB ...) x 2 / (ligand) x 3
Function / homology
Function and homology information


ERBB3:ERBB2 complex / RNA polymerase I core binding / negative regulation of immature T cell proliferation in thymus / positive regulation of transcription by RNA polymerase I / ErbB-3 class receptor binding / peripheral nervous system development / regulation of microtubule-based process / myelination / motor neuron axon guidance / immunoglobulin complex ...ERBB3:ERBB2 complex / RNA polymerase I core binding / negative regulation of immature T cell proliferation in thymus / positive regulation of transcription by RNA polymerase I / ErbB-3 class receptor binding / peripheral nervous system development / regulation of microtubule-based process / myelination / motor neuron axon guidance / immunoglobulin complex / neuromuscular junction development / oligodendrocyte differentiation / enzyme linked receptor protein signaling pathway / negative regulation of ERBB signaling pathway / positive regulation of cell adhesion / phosphatidylinositol 3-kinase signaling / regulation of cell motility / regulation of angiogenesis / positive regulation of protein targeting to membrane / complement activation / basal plasma membrane / immunoglobulin complex, circulating / immunoglobulin receptor binding / phagocytosis, recognition / positive regulation of B cell activation / cellular response to epidermal growth factor stimulus / regulation of ERK1 and ERK2 cascade / positive regulation of epithelial cell proliferation / positive regulation of translation / neuron differentiation / phagocytosis, engulfment / ERBB2 signaling pathway / antigen binding / complement activation, classical pathway / regulation of complement activation / cellular response to growth factor stimulus / positive regulation of GTPase activity / receptor protein-tyrosine kinase / transmembrane receptor protein tyrosine kinase activity / transmembrane signaling receptor activity / positive regulation of kinase activity / B cell receptor signaling pathway / peptidyl-tyrosine phosphorylation / positive regulation of MAP kinase activity / Fc-gamma receptor signaling pathway involved in phagocytosis / receptor-mediated endocytosis / wound healing / Fc-epsilon receptor signaling pathway / retina homeostasis / myelin sheath / transmembrane receptor protein tyrosine kinase signaling pathway / regulation of immune response / heart development / positive regulation of MAPK cascade / leukocyte migration / apical plasma membrane / positive regulation of cell growth / basolateral plasma membrane / protein tyrosine kinase activity / adaptive immune response / protein phosphatase binding / protein C-terminus binding / blood microparticle / early endosome / endosome membrane / receptor complex / cell surface receptor signaling pathway / MAPK cascade / intracellular signal transduction / immune response / positive regulation of protein kinase B signaling / protein heterodimerization activity / positive regulation of protein phosphorylation / protein autophosphorylation / external side of plasma membrane / regulation of transcription by RNA polymerase II / defense response to bacterium / multicellular organism development / innate immune response / protein phosphorylation / positive regulation of cell population proliferation / signal transduction / perinuclear region of cytoplasm / integral component of plasma membrane / extracellular space / extracellular exosome / integral component of membrane / extracellular region / ATP binding / identical protein binding / plasma membrane / nucleus / cytosol
Protein kinase domain / Protein kinase-like domain superfamily / Serine-threonine/tyrosine-protein kinase, catalytic domain / Immunoglobulin/major histocompatibility complex, conserved site / Immunoglobulin C1-set / Immunoglobulin subtype / Furin-like cysteine-rich domain / Furin-like repeat / Immunoglobulin-like domain / Tyrosine-protein kinase, active site ...Protein kinase domain / Protein kinase-like domain superfamily / Serine-threonine/tyrosine-protein kinase, catalytic domain / Immunoglobulin/major histocompatibility complex, conserved site / Immunoglobulin C1-set / Immunoglobulin subtype / Furin-like cysteine-rich domain / Furin-like repeat / Immunoglobulin-like domain / Tyrosine-protein kinase, active site / Receptor L-domain / Growth factor receptor cysteine-rich domain superfamily / Immunoglobulin V-set domain / Immunoglobulin-like fold / Tyrosine protein kinase, EGF/ERB/XmrK receptor / Protein kinase, ATP binding site / Tyrosine-protein kinase, catalytic domain / Growth factor receptor domain 4 / Immunoglobulin-like domain superfamily / Receptor L-domain superfamily
Immunoglobulin kappa constant / Receptor tyrosine-protein kinase erbB-2 / Immunoglobulin gamma-1 heavy chain / IGH@ protein
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.36 Å
AuthorsHao Y / Yu X / Bai Y / Huang X
CitationJournal: 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.
Validation ReportPDB-ID: 6oge

SummaryFull reportAbout validation report
History
DepositionApr 2, 2019-
Header (metadata) releaseMay 1, 2019-
Map releaseMay 15, 2019-
UpdateDec 18, 2019-
Current statusDec 18, 2019Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 4.2
  • Imaged by UCSF Chimera
  • Download
  • Surface view colored by radius
  • Surface level: 4.2
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6oge
  • Surface level: 4.2
  • Imaged by UCSF Chimera
  • Download
Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

Downloads & links

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Map

FileDownload / File: emd_20055.map.gz / Format: CCP4 / Size: 34.3 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesX (Sec.)Y (Row.)Z (Col.)
1.06 Å/pix.
x 208 pix.
= 220.272 Å
1.06 Å/pix.
x 208 pix.
= 220.272 Å
1.06 Å/pix.
x 208 pix.
= 220.272 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.059 Å
Density
Contour LevelBy AUTHOR: 4.2 / Movie #1: 4.2
Minimum - Maximum-10.745524 - 18.676493
Average (Standard dev.)-0.0000000000 (±1)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderZYX
Origin000
Dimensions208208208
Spacing208208208
CellA=B=C: 220.272 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.0591.0591.059
M x/y/z208208208
origin x/y/z0.0000.0000.000
length x/y/z220.272220.272220.272
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ208208208
MAP C/R/S321
start NC/NR/NS000
NC/NR/NS208208208
D min/max/mean-10.74618.676-0.000

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Supplemental data

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Sample components

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Entire Her2 extracellular domain-Trastuzumab Fab-Pertuzumab Fab complex

EntireName: Her2 extracellular domain-Trastuzumab Fab-Pertuzumab Fab complex
Number of components: 12

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Component #1: protein, Her2 extracellular domain-Trastuzumab Fab-Pertuzumab Fab...

ProteinName: Her2 extracellular domain-Trastuzumab Fab-Pertuzumab Fab complex
Recombinant expression: No
SourceSpecies: Homo sapiens (human)

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Component #2: protein, Human HER2 extracellular domain

ProteinName: Human HER2 extracellular domain / Recombinant expression: No
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Homo sapiens (human)

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Component #3: protein, Pertuzumab Fab

ProteinName: Pertuzumab Fab / Recombinant expression: No
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Cricetulus griseus (Chinese hamster)

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Component #4: protein, Trastuzumab Fab

ProteinName: Trastuzumab Fab / Recombinant expression: No
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Cricetulus griseus (Chinese hamster)

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Component #5: protein, Receptor tyrosine-protein kinase erbB-2

ProteinName: Receptor tyrosine-protein kinase erbB-2 / Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 68.536844 kDa
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Homo sapiens (human)

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Component #6: protein, Pertuzumab FAB LIGHT CHAIN

ProteinName: Pertuzumab FAB LIGHT CHAIN / Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 23.548152 kDa
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Cricetulus griseus (Chinese hamster)

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Component #7: protein, Pertuzumab FAB HEAVY CHAIN

ProteinName: Pertuzumab FAB HEAVY CHAIN / Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 23.674486 kDa
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Cricetulus griseus (Chinese hamster)

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Component #8: protein, Trastuzumab FAB LIGHT CHAIN

ProteinName: Trastuzumab FAB LIGHT CHAIN / Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 23.466031 kDa
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Cricetulus griseus (Chinese hamster)

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Component #9: protein, Trastuzumab FAB HEAVY CHAIN

ProteinName: Trastuzumab FAB HEAVY CHAIN / Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 23.42518 kDa
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Cricetulus griseus (Chinese hamster)

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Component #10: ligand, N-ACETYL-D-GLUCOSAMINE

LigandName: N-ACETYL-D-GLUCOSAMINEN-Acetylglucosamine / Number of Copies: 7 / Recombinant expression: No
MassTheoretical: 0.221208 kDa

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Component #11: ligand, BETA-D-MANNOSE

LigandName: BETA-D-MANNOSE / Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 0.180156 kDa

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Component #12: ligand, ALPHA-D-MANNOSE

LigandName: ALPHA-D-MANNOSE / Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 0.180156 kDa

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Experimental details

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Sample preparation

SpecimenSpecimen state: Particle / Method: cryo EM
Sample solutionSpecimen conc.: 2.4 mg/mL / pH: 7.5
VitrificationInstrument: 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
ImagingMicroscope: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Electron dose: 45 e/Å2 / Illumination mode: FLOOD BEAM
LensMagnification: 130000.0 X (nominal) / Cs: 2.7 mm / Imaging mode: BRIGHT FIELD / Defocus: -3500.0 - -1500.0 nm
Specimen HolderModel: OTHER
CameraDetector: GATAN K2 SUMMIT (4k x 4k)

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Image processing

ProcessingMethod: single particle reconstruction / Applied symmetry: C1 (asymmetric) / Number of projections: 398409
3D reconstructionSoftware: cisTEM / Resolution: 4.36 Å / Resolution method: FSC 0.143 CUT-OFF

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Atomic model buiding

Modeling #1Refinement protocol: flexible / Refinement space: REAL
Output model

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