Botulinum neurotoxin A mutants with enhanced ganglioside binding show improved potency and altered ganglioside selectivity
Abstract Botulinum neurotoxins are the causative agents of botulism, a lethal paralytic disease, but are also one of the most commonly used therapeutics for the treatment of numerous neuromuscular conditions. These toxins recognise motor nerve terminals with high specificity and affinity by using a...
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Nature Portfolio
2025-06-01
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| Series: | Communications Chemistry |
| Online Access: | https://doi.org/10.1038/s42004-025-01569-0 |
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| author | Geoffrey Masuyer Andreas Rummel Pål Stenmark |
| author_facet | Geoffrey Masuyer Andreas Rummel Pål Stenmark |
| author_sort | Geoffrey Masuyer |
| collection | DOAJ |
| description | Abstract Botulinum neurotoxins are the causative agents of botulism, a lethal paralytic disease, but are also one of the most commonly used therapeutics for the treatment of numerous neuromuscular conditions. These toxins recognise motor nerve terminals with high specificity and affinity by using a dual binding mechanism involving gangliosides and protein receptors. The initial recognition of gangliosides is crucial for the toxins’ potency. In this study, we employed a synaptosome-binding screening strategy to identify BoNT/A mutants with enhanced ganglioside-binding which translated into improved potency. X-ray crystallography and receptor-binding assays were used to elucidate the molecular mechanisms underlying the increased affinity or altered ganglioside selectivity of these mutants. Our findings provide a basis for the development of BoNT/A variants with enhanced therapeutic potential. |
| format | Article |
| id | doaj-art-ab51541c1a4d41d09bf8f2b2d2fed9a4 |
| institution | OA Journals |
| issn | 2399-3669 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Chemistry |
| spelling | doaj-art-ab51541c1a4d41d09bf8f2b2d2fed9a42025-08-20T02:31:03ZengNature PortfolioCommunications Chemistry2399-36692025-06-018111010.1038/s42004-025-01569-0Botulinum neurotoxin A mutants with enhanced ganglioside binding show improved potency and altered ganglioside selectivityGeoffrey Masuyer0Andreas Rummel1Pål Stenmark2Department of Biochemistry and Biophysics, Stockholm UniversityInstitute of Toxicology, Hannover Medical SchoolDepartment of Biochemistry and Biophysics, Stockholm UniversityAbstract Botulinum neurotoxins are the causative agents of botulism, a lethal paralytic disease, but are also one of the most commonly used therapeutics for the treatment of numerous neuromuscular conditions. These toxins recognise motor nerve terminals with high specificity and affinity by using a dual binding mechanism involving gangliosides and protein receptors. The initial recognition of gangliosides is crucial for the toxins’ potency. In this study, we employed a synaptosome-binding screening strategy to identify BoNT/A mutants with enhanced ganglioside-binding which translated into improved potency. X-ray crystallography and receptor-binding assays were used to elucidate the molecular mechanisms underlying the increased affinity or altered ganglioside selectivity of these mutants. Our findings provide a basis for the development of BoNT/A variants with enhanced therapeutic potential.https://doi.org/10.1038/s42004-025-01569-0 |
| spellingShingle | Geoffrey Masuyer Andreas Rummel Pål Stenmark Botulinum neurotoxin A mutants with enhanced ganglioside binding show improved potency and altered ganglioside selectivity Communications Chemistry |
| title | Botulinum neurotoxin A mutants with enhanced ganglioside binding show improved potency and altered ganglioside selectivity |
| title_full | Botulinum neurotoxin A mutants with enhanced ganglioside binding show improved potency and altered ganglioside selectivity |
| title_fullStr | Botulinum neurotoxin A mutants with enhanced ganglioside binding show improved potency and altered ganglioside selectivity |
| title_full_unstemmed | Botulinum neurotoxin A mutants with enhanced ganglioside binding show improved potency and altered ganglioside selectivity |
| title_short | Botulinum neurotoxin A mutants with enhanced ganglioside binding show improved potency and altered ganglioside selectivity |
| title_sort | botulinum neurotoxin a mutants with enhanced ganglioside binding show improved potency and altered ganglioside selectivity |
| url | https://doi.org/10.1038/s42004-025-01569-0 |
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