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- EMDB-12890: Tetanus neurotoxin HC domain in complex with TT104-Fab1 -

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Basic information

Entry
Database: EMDB / ID: EMD-12890
TitleTetanus neurotoxin HC domain in complex with TT104-Fab1
Map dataTetanus neurotoxin HC domain in complex with TT104-Fab1
Sample
  • Complex: Tetanus neurotoxin HC domain in complex with TT104-Fab1
    • Complex: Tetanus toxinTetanospasmin
      • Protein or peptide: Tetanus toxinTetanospasmin
    • Complex: FAB TT110
      • Protein or peptide: Fab TT104
      • Protein or peptide: Fab TT104
Function / homology
Function and homology information


negative regulation of neurotransmitter secretion / metallopeptidase activity / extracellular region
Similarity search - Function
Clostridium neurotoxin, receptor binding N-terminal / Clostridium neurotoxin, receptor-binding C-terminal / Clostridium neurotoxin, C-terminal receptor binding / Clostridium neurotoxin, N-terminal receptor binding / Kunitz inhibitor STI-like superfamily / Concanavalin A-like lectin/glucanase domain superfamily
Similarity search - Domain/homology
Biological speciesClostridium tetani (bacteria) / Homo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.9 Å
AuthorsGrinzato A / Kandiah E / Zanotti G
CitationJournal: J Clin Invest / Year: 2021
Title: Exceptionally potent human monoclonal antibodies are effective for prophylaxis and treatment of tetanus in mice.
Authors: Marco Pirazzini / Alessandro Grinzato / Davide Corti / Sonia Barbieri / Oneda Leka / Francesca Vallese / Marika Tonellato / Chiara Silacci-Fregni / Luca Piccoli / Eaazhisai Kandiah / ...Authors: Marco Pirazzini / Alessandro Grinzato / Davide Corti / Sonia Barbieri / Oneda Leka / Francesca Vallese / Marika Tonellato / Chiara Silacci-Fregni / Luca Piccoli / Eaazhisai Kandiah / Giampietro Schiavo / Giuseppe Zanotti / Antonio Lanzavecchia / Cesare Montecucco /
Abstract: We used human monoclonal antibodies (humAbs) to study the mechanism of neuron intoxication by tetanus neurotoxin and to evaluate these antibodies as a safe preventive and therapeutic substitute for ...We used human monoclonal antibodies (humAbs) to study the mechanism of neuron intoxication by tetanus neurotoxin and to evaluate these antibodies as a safe preventive and therapeutic substitute for hyperimmune sera to treat tetanus in mice. By screening memory B cells from immune donors, we selected 2 tetanus neurotoxin-specific mAbs with exceptionally high neutralizing activities and extensively characterized them both structurally and functionally. We found that these antibodies interfered with the binding and translocation of the neurotoxin into neurons by interacting with 2 epitopes, whose identification pinpoints crucial events in the cellular pathogenesis of tetanus. Our observations explain the neutralization ability of these antibodies, which we found to be exceptionally potent in preventing experimental tetanus when injected into mice long before the toxin. Moreover, their Fab derivatives neutralized tetanus neurotoxin in post-exposure experiments, suggesting their potential for therapeutic use via intrathecal injection. As such, we believe these humAbs, as well as their Fab derivatives, meet the requirements to be considered for prophylactic and therapeutic use in human tetanus and are ready for clinical trials.
History
DepositionMay 7, 2021-
Header (metadata) releaseOct 27, 2021-
Map releaseOct 27, 2021-
UpdateNov 24, 2021-
Current statusNov 24, 2021Processing site: PDBe / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.4
  • Imaged by UCSF Chimera
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  • Surface view colored by radius
  • Surface level: 0.4
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7oh0
  • Surface level: 0.4
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_12890.png

Downloads & links

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Map

FileDownload / File: emd_12890.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationTetanus neurotoxin HC domain in complex with TT104-Fab1
Voxel sizeX=Y=Z: 0.827 Å
Density
Contour LevelBy AUTHOR: 0.3 / Movie #1: 0.4
Minimum - Maximum-1.0260875 - 1.4598637
Average (Standard dev.)0.00035250335 (±0.0418347)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 248.1 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.8270.8270.827
M x/y/z300300300
origin x/y/z0.0000.0000.000
length x/y/z248.100248.100248.100
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS300300300
D min/max/mean-1.0261.4600.000

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Supplemental data

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Sample components

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Entire : Tetanus neurotoxin HC domain in complex with TT104-Fab1

EntireName: Tetanus neurotoxin HC domain in complex with TT104-Fab1
Components
  • Complex: Tetanus neurotoxin HC domain in complex with TT104-Fab1
    • Complex: Tetanus toxinTetanospasmin
      • Protein or peptide: Tetanus toxinTetanospasmin
    • Complex: FAB TT110
      • Protein or peptide: Fab TT104
      • Protein or peptide: Fab TT104

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Supramolecule #1: Tetanus neurotoxin HC domain in complex with TT104-Fab1

SupramoleculeName: Tetanus neurotoxin HC domain in complex with TT104-Fab1
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all

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Supramolecule #2: Tetanus toxin

SupramoleculeName: Tetanus toxin / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1
Source (natural)Organism: Clostridium tetani (bacteria)

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Supramolecule #3: FAB TT110

SupramoleculeName: FAB TT110 / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #2-#3
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Tetanus toxin

MacromoleculeName: Tetanus toxin / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Clostridium tetani (bacteria)
Molecular weightTheoretical: 50.476918 KDa
SequenceString: EDIDVILKKS TILNLDINND IISDISGFNS SVITYPDAQL VPGINGKAIH LVNNESSEVI VHKAMDIEYN DMFNNFTVSF WLRVPKVSA SHLEQYGTNE YSIISSMKKH SLSIGSGWSV SLKGNNLIWT LKDSAGEVRQ ITFRDLPDKF NAYLANKWVF I TITNDRLS ...String:
EDIDVILKKS TILNLDINND IISDISGFNS SVITYPDAQL VPGINGKAIH LVNNESSEVI VHKAMDIEYN DMFNNFTVSF WLRVPKVSA SHLEQYGTNE YSIISSMKKH SLSIGSGWSV SLKGNNLIWT LKDSAGEVRQ ITFRDLPDKF NAYLANKWVF I TITNDRLS SANLYINGVL MGSAEITGLG AIREDNNITL KLDRCNNNNQ YVSIDKFRIF CKALNPKEIE KLYTSYLSIT FL RDFWGNP LRYDTEYYLI PVASSSKDVQ LKNITDYMYL TNAPSYTNGK LNIYYRRLYN GLKFIIKRYT PNNEIDSFVK SGD FIKLYV SYNNNEHIVG YPKDGNAFNN LDRILRVGYN APGIPLYKKM EAVKLRDLKT YSVQLKLYDD KNASLGLVGT HNGQ IGNDP NRDILIASNW YFNHLKDKIL GCDWYFVPTD EGWTND

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Macromolecule #2: Fab TT104

MacromoleculeName: Fab TT104 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.647295 KDa
SequenceString: QLQLQESGPG LVRPSETLSL TCSVSDDSMG SSTYYWAWIR QPPGKGLEWI GNVYYNGVTY YNSSLESRLT LSIDPSKNQF SLILSSVTA ADTAVYYCAR QADNWFDPWG QGTLVTVSSA STKGPSVFPL APSSKSTSGG TAALGCLVKD YFPEPVTVSW N SGALTSGV ...String:
QLQLQESGPG LVRPSETLSL TCSVSDDSMG SSTYYWAWIR QPPGKGLEWI GNVYYNGVTY YNSSLESRLT LSIDPSKNQF SLILSSVTA ADTAVYYCAR QADNWFDPWG QGTLVTVSSA STKGPSVFPL APSSKSTSGG TAALGCLVKD YFPEPVTVSW N SGALTSGV HTFPAVLQSS GLYSLSSVVT VPSSSLGTQT YICNVNHKPS NTKVDKRVEP KSC

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Macromolecule #3: Fab TT104

MacromoleculeName: Fab TT104 / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.462094 KDa
SequenceString: IMMTQSPATL SVSPGERATL SCRASQSVGS DLAWYQQKPG QAPRLLIYGA SYRATGIPAR FSGGGSGTEF TLTISSMQSE DFAVYYCQQ YYNWPPYTFG QGTKVEIKRT VAAPSVFIFP PSDEQLKSGT ASVVCLLNNF YPREAKVQWK VDNALQSGNS Q ESVTEQDS ...String:
IMMTQSPATL SVSPGERATL SCRASQSVGS DLAWYQQKPG QAPRLLIYGA SYRATGIPAR FSGGGSGTEF TLTISSMQSE DFAVYYCQQ YYNWPPYTFG QGTKVEIKRT VAAPSVFIFP PSDEQLKSGT ASVVCLLNNF YPREAKVQWK VDNALQSGNS Q ESVTEQDS KDSTYSLSST LTLSKADYEK HKVYACEVTH QGLSSPVTKS FNRGEC

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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: 7.6
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 40.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.9 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 98170

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