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- PDB-7oh0: Tetanus neurotoxin HC domain in complex with TT104-Fab1 -

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Basic information

Entry
Database: PDB / ID: 7oh0
TitleTetanus neurotoxin HC domain in complex with TT104-Fab1
Components
  • (Fab TT104) x 2
  • Tetanus toxinTetanospasmin
KeywordsTOXIN / tetanus / tetanus neurotoxin / humAbs / monoclonal antibody / tetanus prophylaxis / spastic paralysis / tetanus immunoglobulin / TIG
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, N-terminal receptor binding / Clostridium neurotoxin, receptor-binding C-terminal / Clostridium neurotoxin, C-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)
MethodELECTRON MICROSCOPY / single 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, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 27, 2021Provider: repository / Type: Initial release
Revision 1.1Nov 3, 2021Group: Data collection / Source and taxonomy
Category: em_admin / em_entity_assembly_naturalsource / pdbx_database_proc
Item: _em_admin.last_update / _em_entity_assembly_naturalsource.entity_assembly_id
Revision 1.2Nov 24, 2021Group: Database references / Category: citation / Item: _citation.journal_volume / _citation.title

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Structure visualization

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Assembly

Deposited unit
A: Tetanus toxin
C: Fab TT104
B: Fab TT104


Theoretical massNumber of molelcules
Total (without water)97,5863
Polymers97,5863
Non-polymers00
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: surface plasmon resonance
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area5340 Å2
ΔGint-34 kcal/mol
Surface area39280 Å2

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Components

#1: Protein Tetanus toxin / Tetanospasmin


Mass: 50476.918 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Clostridium tetani (bacteria) / References: UniProt: C4PD05
#2: Antibody Fab TT104


Mass: 23647.295 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human)
#3: Antibody Fab TT104


Mass: 23462.094 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human)

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

Component
IDNameTypeEntity IDParent-IDSource
1Tetanus neurotoxin HC domain in complex with TT104-Fab1COMPLEX#1-#30NATURAL
2Tetanus toxinTetanospasminCOMPLEX#11NATURAL
3FAB TT110COMPLEX#2-#31NATURAL
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
12Clostridium tetani (bacteria)1513
23Homo sapiens (human)9606
Buffer solutionpH: 7.6
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy
Image recordingElectron dose: 40 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.15.2_3472: / Classification: refinement
CTF correctionType: NONE
3D reconstructionResolution: 3.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 98170 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0046992
ELECTRON MICROSCOPYf_angle_d0.7549512
ELECTRON MICROSCOPYf_dihedral_angle_d9.6674152
ELECTRON MICROSCOPYf_chiral_restr0.0471054
ELECTRON MICROSCOPYf_plane_restr0.0061219

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