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- PDB-7oh1: Tetanus neurotoxin LC-HN domain in complex with TT110-Fab1 -

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Basic information

Entry
Database: PDB / ID: 7oh1
TitleTetanus neurotoxin LC-HN domain in complex with TT110-Fab1
Components
  • (FAB TT110) 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 / protein transmembrane transporter activity / metalloendopeptidase activity / toxin activity / zinc ion binding / extracellular region
Similarity search - Function
Clostridium neurotoxin, translocation / Clostridium neurotoxin, Translocation domain / Clostridium neurotoxin, translocation domain / Clostridial neurotoxin zinc protease / Botulinum/Tetanus toxin, catalytic chain / 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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 8 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
E: FAB TT110
D: FAB TT110


Theoretical massNumber of molelcules
Total (without water)147,2463
Polymers147,2463
Non-polymers00
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: surface plasmon resonance
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area5600 Å2
ΔGint-35 kcal/mol
Surface area58860 Å2

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Components

#1: Protein Tetanus toxin / Tetanospasmin


Mass: 99924.320 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Clostridium tetani (bacteria) / References: UniProt: Q93N27
#2: Antibody FAB TT110


Mass: 24298.252 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human)
#3: Antibody FAB TT110


Mass: 23023.553 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 LC-HN domain in complex with TT110-Fab1COMPLEXall0NATURAL
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

CTF correctionType: NONE
3D reconstructionResolution: 8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 98170 / Symmetry type: POINT

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