|Entry||Database: PDB / ID: 7oh0|
|Title||Tetanus neurotoxin HC domain in complex with TT104-Fab1|
|Keywords||TOXIN / 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
Similarity search - Component
|Biological species||Clostridium tetani (bacteria)|
Homo sapiens (human)
|Method||ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.9 Å|
|Authors||Grinzato, A. / Kandiah, E. / Zanotti, G.|
|Citation||Journal: 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.
|Structure viewer||Molecule: |
Downloads & links
A: Tetanus toxin
C: Fab TT104
B: Fab TT104
|#1: Protein|| |
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|| |
Mass: 23647.295 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human)
|#3: Antibody|| |
Mass: 23462.094 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human)
|Experiment||Method: ELECTRON MICROSCOPY|
|EM experiment||Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction|
|Buffer solution||pH: 7.6|
|Specimen||Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES|
|Vitrification||Cryogen name: ETHANE|
-Electron microscopy imaging
Model: Titan Krios / Image courtesy: FEI Company
|Microscopy||Model: FEI TITAN KRIOS|
|Electron gun||Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM|
|Electron lens||Mode: BRIGHT FIELDBright-field microscopy|
|Image recording||Electron dose: 40 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)|
|Software||Name: PHENIX / Version: 1.15.2_3472: / Classification: refinement|
|CTF correction||Type: NONE|
|3D reconstruction||Resolution: 3.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 98170 / Symmetry type: POINT|
|Refine LS restraints|
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