Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: UMLS:C0019621 (
Langerhans cell histiocytosis
)
3,250
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Botulinum neurotoxin serotype E (
BoNT
/E) is one of the major causes of human botulism, which is a life-threatening disease caused by flaccid paralysis of muscles. After receptor-mediated toxin internalization into motor neurons, the translocation domain (H
N
) of
BoNT
/E transforms into a protein channel upon vesicle acidification in endosomes and delivers its protease domain (LC) across membrane to enter the neuronal cytosol. It is believed that the rapid onset of
BoNT
/E intoxication compared to other
BoNT
serotypes is related to its swift internalization and translocation. We recently identified two neutralizing single-domain camelid antibodies (VHHs) against
BoNT
/E1 termed JLE-E5 and JLE-E9. Here, we report the crystal structures of these two VHHs bound to the
LCH
N
domain of
BoNT
/E1. The structures reveal that these VHHs recognize two distinct epitopes that are partially overlapping with the putative transmembrane regions on H
N
, and therefore could physically block membrane association of
BoNT
/E1. This is confirmed by our in vitro studies, which show that these VHHs inhibit the structural change of
BoNT
/E1 at acidic pH and interfere with
BoNT
/E1 association with lipid vesicles. Therefore, these two VHHs neutralize
BoNT
/E1 by preventing the transmembrane delivery of LC. Furthermore, structure-based sequence analyses show that the 3-dimensional epitopes of these two VHHs are largely conserved across many
BoNT
/E subtypes, suggesting a broad-spectrum protection against the
BoNT
/E family. In summary, this work improves our understanding of the membrane translocation mechanism of
BoNT
/E and paves the way for developing VHHs as diagnostics or therapeutics for the treatment of
BoNT
/E intoxication.
...
PMID:Two VHH Antibodies Neutralize Botulinum Neurotoxin E1 by Blocking Its Membrane Translocation in Host Cells. 3299 61
