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- EMDB-47571: Fully human monoclonal antibody targeting the cysteine-rich subst... -

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Basic information

Entry
Database: EMDB / ID: EMD-47571
TitleFully human monoclonal antibody targeting the cysteine-rich substrate-interacting region of ADAM17 on cancer cells.
Map data
Sample
  • Complex: Complex of ADAM17 disintegrin-cysteine rich domain
    • Protein or peptide: heavy chain of monoclonal antibody C12
    • Protein or peptide: light chain monoclonal antibody C12
    • Protein or peptide: Disintegrin and metalloproteinase domain-containing protein 17
Keywordsinhibitor / complex / ONCOPROTEIN / ANTITUMOR PROTEIN / ANTITUMOR PROTEIN-IMMUNE SYSTEM complex
Function / homology
Function and homology information


ADAM 17 endopeptidase / regulation of mast cell apoptotic process / signal release / metalloendopeptidase activity involved in amyloid precursor protein catabolic process / cellular response to high density lipoprotein particle stimulus / positive regulation of epidermal growth factor-activated receptor activity / Constitutive Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation Mutant / interleukin-6 receptor binding / Notch receptor processing / tumor necrosis factor binding ...ADAM 17 endopeptidase / regulation of mast cell apoptotic process / signal release / metalloendopeptidase activity involved in amyloid precursor protein catabolic process / cellular response to high density lipoprotein particle stimulus / positive regulation of epidermal growth factor-activated receptor activity / Constitutive Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation Mutant / interleukin-6 receptor binding / Notch receptor processing / tumor necrosis factor binding / positive regulation of T cell chemotaxis / TNF signaling / germinal center formation / positive regulation of leukocyte chemotaxis / Release of Hh-Np from the secreting cell / Regulated proteolysis of p75NTR / commissural neuron axon guidance / positive regulation of tumor necrosis factor-mediated signaling pathway / neutrophil mediated immunity / Notch binding / wound healing, spreading of epidermal cells / negative regulation of cold-induced thermogenesis / CD163 mediating an anti-inflammatory response / positive regulation of vascular endothelial cell proliferation / positive regulation of epidermal growth factor receptor signaling pathway / cell adhesion mediated by integrin / Signaling by EGFR / amyloid precursor protein catabolic process / cytokine binding / Collagen degradation / membrane protein ectodomain proteolysis / positive regulation of cyclin-dependent protein serine/threonine kinase activity / positive regulation of blood vessel endothelial cell migration / positive regulation of G1/S transition of mitotic cell cycle / Growth hormone receptor signaling / Nuclear signaling by ERBB4 / positive regulation of chemokine production / spleen development / Notch signaling pathway / Constitutive Signaling by NOTCH1 HD Domain Mutants / Activated NOTCH1 Transmits Signal to the Nucleus / B cell differentiation / cell motility / PDZ domain binding / negative regulation of transforming growth factor beta receptor signaling pathway / protein processing / metalloendopeptidase activity / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / SH3 domain binding / metallopeptidase activity / positive regulation of tumor necrosis factor production / integrin binding / actin cytoskeleton / peptidase activity / T cell differentiation in thymus / positive regulation of cell growth / endopeptidase activity / response to lipopolysaccharide / response to hypoxia / cell adhesion / defense response to Gram-positive bacterium / positive regulation of cell migration / response to xenobiotic stimulus / membrane raft / apical plasma membrane / endoplasmic reticulum lumen / Golgi membrane / positive regulation of cell population proliferation / cell surface / proteolysis / membrane / metal ion binding / plasma membrane / cytosol / cytoplasm
Similarity search - Function
ADAM17, membrane-proximal domain / Membrane-proximal domain, switch, for ADAM17 / Metallo-peptidase family M12 / ADAM10/ADAM17 catalytic domain / : / Disintegrin / Disintegrin domain profile. / Homologues of snake disintegrins / Disintegrin domain / Disintegrin domain superfamily ...ADAM17, membrane-proximal domain / Membrane-proximal domain, switch, for ADAM17 / Metallo-peptidase family M12 / ADAM10/ADAM17 catalytic domain / : / Disintegrin / Disintegrin domain profile. / Homologues of snake disintegrins / Disintegrin domain / Disintegrin domain superfamily / Peptidase M12B, ADAM/reprolysin / ADAM type metalloprotease domain profile. / Metallopeptidase, catalytic domain superfamily / Neutral zinc metallopeptidases, zinc-binding region signature.
Similarity search - Domain/homology
Disintegrin and metalloproteinase domain-containing protein 17
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.15 Å
AuthorsSaha N / De La Cruz MJ / Goldgur Y / Nikolov DB
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI) United States
CitationJournal: Biomed Pharmacother / Year: 2024
Title: Fully human monoclonal antibody targeting the cysteine-rich substrate-interacting region of ADAM17 on cancer cells.
Authors: Nayanendu Saha / Sang Gyu Lee / Eeva-Christine Brockmann / M Jason de la Cruz / Yehuda Goldgur / Rachelle P Mendoza / Elisa de Stanchina / Tanzy M Love / Josh Marvald / Yan Xu / Kai Xu / ...Authors: Nayanendu Saha / Sang Gyu Lee / Eeva-Christine Brockmann / M Jason de la Cruz / Yehuda Goldgur / Rachelle P Mendoza / Elisa de Stanchina / Tanzy M Love / Josh Marvald / Yan Xu / Kai Xu / Juha P Himanen / Urpo Lamminmäki / Darren Veach / Dimitar B Nikolov /
Abstract: ADAM17 sheds EGFR/erbB ligands and triggers oncogenic pathways that lead to the progression of solid tumors. We targeted the ADAM17 disintegrin and cysteine rich domain region (D+C) to generate a ...ADAM17 sheds EGFR/erbB ligands and triggers oncogenic pathways that lead to the progression of solid tumors. We targeted the ADAM17 disintegrin and cysteine rich domain region (D+C) to generate a panel of single-chain antibody fragments (scFvs) that selectively bind to the D or C domains of ADAM17, but not of ADAM10 or ADAM19. From the panel, we selected one scFv, referred to as C12, based on its high binding affinity towards the target, and re-formatted it to a full IgG for further studies. High-resolution cryo-electron microscopy studies documented that the mAb binds to the ADAM17 C-domain that in ADAM proteases, notably ADAM10 and ADAM17, is known to impart substrate-specificity. The C12 mAb significantly inhibited EGFR phosphorylation in cancer cell lines by hindering the cleavage of EGFR ligands tethered to the cell surface. This inhibition provides a mechanism for potential anti-tumor effects, and indeed C12 diminished the viability of a variety of EGFR-expressing cancer cell lines. Cell-based ELISA studies revealed that C12 preferentially bound to activated ADAM17 present on tumor cells, as compared to the autoinhibited ADAM17 that is the predominant form on HEK293 and other non-tumor cells. C12 also exhibited tumor growth inhibition in an ovarian cancer xenograft mouse model. Consistent with its selective tumor cell binding in vitro, radioimmuno PET (positron emission tomography) imaging with Zr-DFO-C12 in mouse xenograft models confirmed tumoral accumulation of the C12 mAb.
History
DepositionOct 30, 2024-
Header (metadata) releaseNov 20, 2024-
Map releaseNov 20, 2024-
UpdateNov 20, 2024-
Current statusNov 20, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_47571.png

Downloads & links

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Map

FileDownload / File: emd_47571.map.gz / Format: CCP4 / Size: 4.9 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesX (Sec.)Y (Row.)Z (Col.)
0.83 Å/pix.
x 77 pix.
= 63.563 Å		0.83 Å/pix.
x 99 pix.
= 81.725 Å		0.83 Å/pix.
x 168 pix.
= 138.684 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

generated in cubic-lattice coordinate

Voxel sizeX=Y=Z: 0.8255 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.08
Minimum - Maximum-0.3897956 - 0.6973817
Average (Standard dev.)0.009194027 (±0.049550895)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderZYX
Origin13996158
Dimensions9916877
Spacing7799168
CellA: 63.5635 Å / B: 81.7245 Å / C: 138.684 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_47571_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_47571_half_map_2.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Complex of ADAM17 disintegrin-cysteine rich domain

EntireName: Complex of ADAM17 disintegrin-cysteine rich domain
Components
  • Complex: Complex of ADAM17 disintegrin-cysteine rich domain
    • Protein or peptide: heavy chain of monoclonal antibody C12
    • Protein or peptide: light chain monoclonal antibody C12
    • Protein or peptide: Disintegrin and metalloproteinase domain-containing protein 17

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Supramolecule #1: Complex of ADAM17 disintegrin-cysteine rich domain

SupramoleculeName: Complex of ADAM17 disintegrin-cysteine rich domain / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: heavy chain of monoclonal antibody C12

MacromoleculeName: heavy chain of monoclonal antibody C12 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.02983 KDa
Recombinant expressionOrganism: Spodoptera (butterflies/moths)
SequenceString: EVQLLESGGG LVQPGGSLRL SCAASGFTFS GYWMHWVRQA PGKGLEWVSR ITYNGTTDYA DSVKGRFTIS RDNSKNTLYL QMNSLRAED TAVYYCARGW LDVWGQGTLV TVSSASTKGP SVFPLAPSSK STSGGTAALG CLVKDYFPEP VTVSWNSGAL T SGVHTFPA ...String:
EVQLLESGGG LVQPGGSLRL SCAASGFTFS GYWMHWVRQA PGKGLEWVSR ITYNGTTDYA DSVKGRFTIS RDNSKNTLYL QMNSLRAED TAVYYCARGW LDVWGQGTLV TVSSASTKGP SVFPLAPSSK STSGGTAALG CLVKDYFPEP VTVSWNSGAL T SGVHTFPA VLQSSGLYSL SSVVTVPSSS LGTQTYICNV NHKPSNTKVD KKVEPKSC

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Macromolecule #2: light chain monoclonal antibody C12

MacromoleculeName: light chain monoclonal antibody C12 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.439961 KDa
Recombinant expressionOrganism: Spodoptera (butterflies/moths)
SequenceString: EIVLTQSPGT LSLSPGERAT LSCRASQSVS SSNLAWYQQK PGQAPRLLIY GASSRATGVP DRFSGSGSGT DFTLTISRLE PEDFAVYYC QQSYSLPWTF GQGTKVEIKR TVAAPSVFIF PPSDEQLKSG TASVVCLLNN FYPREAKVQW KVDNALQSGN S QESVTEQD ...String:
EIVLTQSPGT LSLSPGERAT LSCRASQSVS SSNLAWYQQK PGQAPRLLIY GASSRATGVP DRFSGSGSGT DFTLTISRLE PEDFAVYYC QQSYSLPWTF GQGTKVEIKR TVAAPSVFIF PPSDEQLKSG TASVVCLLNN FYPREAKVQW KVDNALQSGN S QESVTEQD SKDSTYSLSS TLTLSKADYE KHKVYACEVT HQGLSSPVTK SFNRGEC

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Macromolecule #3: Disintegrin and metalloproteinase domain-containing protein 17

MacromoleculeName: Disintegrin and metalloproteinase domain-containing protein 17
type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO / EC number: ADAM 17 endopeptidase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 12.579383 KDa
Recombinant expressionOrganism: Spodoptera (butterflies/moths)
SequenceString:
AQKKCQEAIN ATCKGVSYCT GNSSECPPPG NAEDDTVCLD LGKCKDGKCI PFCEREQQLE SCACNETDNS CKVCCRDLSG RCVPYVDAE QKNLFLRKGK PCTVGFCDMN GKCEKR

UniProtKB: Disintegrin and metalloproteinase domain-containing protein 17

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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

BufferpH: 7.4
VitrificationCryogen name: NITROGEN

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 65.9 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.0 µm / Nominal defocus min: 0.5 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

8gh4

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.15 Å / Resolution method: OTHER / Number images used: 898088
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: NOT APPLICABLE
FSC plot (resolution estimation)

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