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- EMDB-17993: Atomic structure and conformational variability of the HER2-Trast... -

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Basic information

Entry
Database: EMDB / ID: EMD-17993
TitleAtomic structure and conformational variability of the HER2-Trastuzumab-Pertuzumab complex
Map dataComposite map visible in figure 1 d
Sample
  • Complex: Ternary complex of her2-trastuzumab-pertuzumab Fabs
    • Protein or peptide: Trastuzumab Fab light chain
    • Protein or peptide: Trastuzumab Fab heavy chain
    • Protein or peptide: Pertuzumab Fab light chain
    • Protein or peptide: Pertuzumab Fab heavy chain
  • Protein or peptide: Receptor tyrosine-protein kinase erbB-2
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
KeywordsErbB-2 / Pertuzumab / Trastuzumab / Ternary complex / Protein / Flexibility / Continuous conformation / Cryo-EM / Single particle analysis / STRUCTURAL PROTEIN
Function / homology
Function and homology information


negative regulation of immature T cell proliferation in thymus / ERBB3:ERBB2 complex / ERBB2-ERBB4 signaling pathway / GRB7 events in ERBB2 signaling / immature T cell proliferation in thymus / RNA polymerase I core binding / semaphorin receptor complex / regulation of microtubule-based process / ErbB-3 class receptor binding / Sema4D induced cell migration and growth-cone collapse ...negative regulation of immature T cell proliferation in thymus / ERBB3:ERBB2 complex / ERBB2-ERBB4 signaling pathway / GRB7 events in ERBB2 signaling / immature T cell proliferation in thymus / RNA polymerase I core binding / semaphorin receptor complex / regulation of microtubule-based process / ErbB-3 class receptor binding / Sema4D induced cell migration and growth-cone collapse / motor neuron axon guidance / neurotransmitter receptor localization to postsynaptic specialization membrane / PLCG1 events in ERBB2 signaling / ERBB2-EGFR signaling pathway / positive regulation of Rho protein signal transduction / neuromuscular junction development / ERBB2 Activates PTK6 Signaling / 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 / ERBB2 Regulates Cell Motility / semaphorin-plexin signaling pathway / PI3K events in ERBB2 signaling / positive regulation of protein targeting to membrane / positive regulation of cell adhesion / regulation of angiogenesis / coreceptor activity / Schwann cell development / Signaling by ERBB2 / cellular response to epidermal growth factor stimulus / myelination / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / GRB2 events in ERBB2 signaling / Downregulation of ERBB2:ERBB3 signaling / transmembrane receptor protein tyrosine kinase activity / neurogenesis / SHC1 events in ERBB2 signaling / Constitutive Signaling by Overexpressed ERBB2 / basal plasma membrane / regulation of ERK1 and ERK2 cascade / positive regulation of translation / phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of epithelial cell proliferation / Signaling by ERBB2 TMD/JMD mutants / positive regulation of MAP kinase activity / neuromuscular junction / 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 / Downregulation of ERBB2 signaling / ruffle membrane / peptidyl-tyrosine phosphorylation / cell surface receptor protein tyrosine kinase signaling pathway / Constitutive Signaling by Aberrant PI3K in Cancer / transmembrane signaling receptor activity / PIP3 activates AKT signaling / presynaptic membrane / myelin sheath / heart development / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / RAF/MAP kinase cascade / positive regulation of cell growth / basolateral plasma membrane / protein tyrosine kinase activity / positive regulation of MAPK cascade / cell surface receptor signaling pathway / receptor complex / early endosome / endosome membrane / intracellular signal transduction / positive regulation of protein phosphorylation / apical plasma membrane / protein heterodimerization activity / protein phosphorylation / signaling receptor binding / positive regulation of cell population proliferation / negative regulation of apoptotic process / perinuclear region of cytoplasm / signal transduction / nucleoplasm / ATP binding / membrane / identical protein binding / nucleus / plasma membrane
Similarity search - Function
: / Epidermal growth factor receptor transmembrane-juxtamembrane segment / Tyrosine protein kinase, EGF/ERB/XmrK receptor / Growth factor receptor domain 4 / Growth factor receptor domain IV / Receptor L-domain / Furin-like cysteine-rich domain / Receptor L-domain superfamily / Furin-like cysteine rich region / Receptor L domain ...: / Epidermal growth factor receptor transmembrane-juxtamembrane segment / Tyrosine protein kinase, EGF/ERB/XmrK receptor / Growth factor receptor domain 4 / Growth factor receptor domain IV / Receptor L-domain / Furin-like cysteine-rich domain / Receptor L-domain superfamily / Furin-like cysteine rich region / Receptor L domain / Furin-like repeat / Furin-like repeats / Growth factor receptor cysteine-rich domain superfamily / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / Tyrosine-protein kinase, active site / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Receptor tyrosine-protein kinase erbB-2
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.17 Å
AuthorsRuedas R / Vuillemot R / Tubiana T / Winter JM / Pieri L / Arteni AA / Samson C / Jonic J / Mathieu M / Bressanelli S
Funding support France, 2 items
OrganizationGrant numberCountry
Centre National de la Recherche Scientifique (CNRS) France
Other private
CitationJournal: To Be Published
Title: Atomic structure and conformational variability of the HER2-Trastuzumab-Pertuzumab complex
Authors: Ruedas R / Vuillemot R / Tubiana T / Winter JM / Pieri L / Arteni AA / Samson C / Jonic J / Mathieu M / Bressanelli S
History
DepositionJul 20, 2023-
Header (metadata) releaseFeb 21, 2024-
Map releaseFeb 21, 2024-
UpdateFeb 21, 2024-
Current statusFeb 21, 2024Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_17993.png

Downloads & links

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Map

FileDownload / File: emd_17993.map.gz / Format: CCP4 / Size: 83.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationComposite map visible in figure 1 d
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.16 Å/pix.
x 280 pix.
= 324.8 Å		1.16 Å/pix.
x 280 pix.
= 324.8 Å		1.16 Å/pix.
x 280 pix.
= 324.8 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.16 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 14.0
Minimum - Maximum-34.793903 - 63.028584000000002
Average (Standard dev.)0.0017327087 (±1.1724592)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions280280280
Spacing280280280
CellA=B=C: 324.8 Å
α=β=γ: 90.0 °

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Supplemental data

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Sample components

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Entire : Ternary complex of her2-trastuzumab-pertuzumab Fabs

EntireName: Ternary complex of her2-trastuzumab-pertuzumab Fabs
Components
  • Complex: Ternary complex of her2-trastuzumab-pertuzumab Fabs
    • Protein or peptide: Trastuzumab Fab light chain
    • Protein or peptide: Trastuzumab Fab heavy chain
    • Protein or peptide: Pertuzumab Fab light chain
    • Protein or peptide: Pertuzumab Fab heavy chain
  • Protein or peptide: Receptor tyrosine-protein kinase erbB-2
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: Ternary complex of her2-trastuzumab-pertuzumab Fabs

SupramoleculeName: Ternary complex of her2-trastuzumab-pertuzumab Fabs / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#4
Details: Fab fragment from trastuzumab and pertuzumab linked to the extracellular domain of erbb2 (her2)
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 171.364 KDa

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Macromolecule #1: Trastuzumab Fab light chain

MacromoleculeName: Trastuzumab Fab light chain / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.466031 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString: DIQMTQSPSS LSASVGDRVT ITCRASQDVN TAVAWYQQKP GKAPKLLIYS ASFLYSGVPS RFSGSRSGTD FTLTISSLQP EDFATYYCQ QHYTTPPTFG QGTKVEIKRT VAAPSVFIFP PSDEQLKSGT ASVVCLLNNF YPREAKVQWK VDNALQSGNS Q ESVTEQDS ...String:
DIQMTQSPSS LSASVGDRVT ITCRASQDVN TAVAWYQQKP GKAPKLLIYS ASFLYSGVPS RFSGSRSGTD FTLTISSLQP EDFATYYCQ QHYTTPPTFG QGTKVEIKRT VAAPSVFIFP PSDEQLKSGT ASVVCLLNNF YPREAKVQWK VDNALQSGNS Q ESVTEQDS KDSTYSLSST LTLSKADYEK HKVYACEVTH QGLSSPVTKS FNRGEC

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Macromolecule #2: Trastuzumab Fab heavy chain

MacromoleculeName: Trastuzumab Fab heavy chain / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.42518 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString: EVQLVESGGG LVQPGGSLRL SCAASGFNIK DTYIHWVRQA PGKGLEWVAR IYPTNGYTRY ADSVKGRFTI SADTSKNTAY LQMNSLRAE DTAVYYCSRW GGDGFYAMDY WGQGTLVTVS SASTKGPSVF PLAPSSKSTS GGTAALGCLV KDYFPEPVTV S WNSGALTS ...String:
EVQLVESGGG LVQPGGSLRL SCAASGFNIK DTYIHWVRQA PGKGLEWVAR IYPTNGYTRY ADSVKGRFTI SADTSKNTAY LQMNSLRAE DTAVYYCSRW GGDGFYAMDY WGQGTLVTVS SASTKGPSVF PLAPSSKSTS GGTAALGCLV KDYFPEPVTV S WNSGALTS GVHTFPAVLQ SSGLYSLSSV VTVPSSSLGT QTYICNVNHK PSNTKVDKKV EP

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Macromolecule #3: Pertuzumab Fab light chain

MacromoleculeName: Pertuzumab Fab light chain / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.548152 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString: DIQMTQSPSS LSASVGDRVT ITCKASQDVS IGVAWYQQKP GKAPKLLIYS ASYRYTGVPS RFSGSGSGTD FTLTISSLQP EDFATYYCQ QYYIYPYTFG QGTKVEIKRT VAAPSVFIFP PSDEQLKSGT ASVVCLLNNF YPREAKVQWK VDNALQSGNS Q ESVTEQDS ...String:
DIQMTQSPSS LSASVGDRVT ITCKASQDVS IGVAWYQQKP GKAPKLLIYS ASYRYTGVPS RFSGSGSGTD FTLTISSLQP EDFATYYCQ QYYIYPYTFG QGTKVEIKRT VAAPSVFIFP PSDEQLKSGT ASVVCLLNNF YPREAKVQWK VDNALQSGNS Q ESVTEQDS KDSTYSLSST LTLSKADYEK HKVYACEVTH QGLSSPVTKS FNRGEC

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Macromolecule #4: Pertuzumab Fab heavy chain

MacromoleculeName: Pertuzumab Fab heavy chain / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.674486 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString: EVQLVESGGG LVQPGGSLRL SCAASGFTFT DYTMDWVRQA PGKGLEWVAD VNPNSGGSIY NQRFKGRFTL SVDRSKNTLY LQMNSLRAE DTAVYYCARN LGPSFYFDYW GQGTLVTVSS ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS W NSGALTSG ...String:
EVQLVESGGG LVQPGGSLRL SCAASGFTFT DYTMDWVRQA PGKGLEWVAD VNPNSGGSIY NQRFKGRFTL SVDRSKNTLY LQMNSLRAE DTAVYYCARN LGPSFYFDYW GQGTLVTVSS ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS W NSGALTSG VHTFPAVLQS SGLYSLSSVV TVPSSSLGTQ TYICNVNHKP SNTKVDKKVE PKSC

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Macromolecule #5: Receptor tyrosine-protein kinase erbB-2

MacromoleculeName: Receptor tyrosine-protein kinase erbB-2 / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 68.794086 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: TQVCTGTDMK LRLPASPETH LDMLRHLYQG CQVVQGNLEL TYLPTNASLS FLQDIQEVQG YVLIAHNQVR QVPLQRLRIV RGTQLFEDN YALAVLDNGD PLNNTTPVTG ASPGGLRELQ LRSLTEILKG GVLIQRNPQL CYQDTILWKD IFHKNNQLAL T LIDTNRSR ...String:
TQVCTGTDMK LRLPASPETH LDMLRHLYQG CQVVQGNLEL TYLPTNASLS FLQDIQEVQG YVLIAHNQVR QVPLQRLRIV RGTQLFEDN YALAVLDNGD PLNNTTPVTG ASPGGLRELQ LRSLTEILKG GVLIQRNPQL CYQDTILWKD IFHKNNQLAL T LIDTNRSR ACHPCSPMCK GSRCWGESSE DCQSLTRTVC AGGCARCKGP LPTDCCHEQC AAGCTGPKHS DCLACLHFNH SG ICELHCP ALVTYNTDTF ESMPNPEGRY TFGASCVTAC PYNYLSTDVG SCTLVCPLHN QEVTAEDGTQ RCEKCSKPCA RVC YGLGME HLREVRAVTS ANIQEFAGCK KIFGSLAFLP ESFDGDPASN TAPLQPEQLQ VFETLEEITG YLYISAWPDS LPDL SVFQN LQVIRGRILH NGAYSLTLQG LGISWLGLRS LRELGSGLAL IHHNTHLCFV HTVPWDQLFR NPHQALLHTA NRPED ECVG EGLACHQLCA RGHCWGPGPT QCVNCSQFLR GQECVEECRV LQGLPREYVN ARHCLPCHPE CQPQNGSVTC FGPEAD QCV ACAHYKDPPF CVARCPSGVK PDLSYMPIWK FPDEEGACQP CPINCTHSCV DLDDKGCPAE Q

UniProtKB: Receptor tyrosine-protein kinase erbB-2

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Macromolecule #7: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 7 / Number of copies: 3 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration0.12 mg/mL
BufferpH: 7.5
Component:
ConcentrationFormulaName
10.0 mMC8H18N2O4SHEPES
150.0 mMNaClSodium chloridesodium chloride
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 400 / Support film - Material: CARBON / Support film - topology: CONTINUOUS / Support film - Film thickness: 2 / Pretreatment - Type: PLASMA CLEANING / Pretreatment - Time: 20 sec. / Pretreatment - Atmosphere: AIR / Details: 12 mAu
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 288.15 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS GLACIOS
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Cs: 2.1 mm / Nominal defocus max: 2.6 µm / Nominal defocus min: 0.8 µm / Nominal magnification: 240000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: HELIUM
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Digitization - Dimensions - Width: 4096 pixel / Digitization - Dimensions - Height: 4096 pixel / Number grids imaged: 1 / Number real images: 8928 / Average exposure time: 4.71 sec. / Average electron dose: 60.0 e/Å2

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Image processing

Particle selectionNumber selected: 2954825
Startup modelType of model: OTHER
Details: 1z8z and 1s78 pdb were used to build the startup model.
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.1.2)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.1.2)
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.17 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4.1.2) / Number images used: 711008
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial model
ChainPDB ID
source_name: AlphaFold, initial_model_type: in silico model
source_name: PDB, initial_model_type: experimental model

1n8z

chain_id: C, source_name: PDB, initial_model_type: experimental model

1s78

chain_id: D, source_name: PDB, initial_model_type: experimental model

1s78

source_name: PDB, initial_model_type: experimental model

6oge

RefinementSpace: REAL / Protocol: RIGID BODY FIT
Output model

PDB-8pwh:
Atomic structure and conformational variability of the HER2-Trastuzumab-Pertuzumab complex

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