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Engineered botulinum neurotoxin B with improved efficacy for targeting human receptors
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Umeå University, Sweden.
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Number of Authors: 13
2017 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, 53Article in journal (Refereed) Published
Abstract [en]

Botulinum neurotoxin B is a Food and Drug Administration-approved therapeutic toxin. However, it has lower binding affinity toward the human version of its major receptor, synaptotagmin II (h-Syt II), compared to mouse Syt II, because of a residue difference. Increasing the binding affinity to h-Syt II may improve botulinum neurotoxin B's therapeutic efficacy and reduce adverse effects. Here we utilized the bacterial adenylate cyclase two-hybrid method and carried out a saturation mutagenesis screen in the Syt II-binding pocket of botulinum neurotoxin B. The screen identifies E1191 as a key residue: replacing it with M/C/V/Q enhances botulinum neurotoxin B binding to human synaptotagmin II. Adding S1199Y/W or W1178Q as a secondary mutation further increases binding affinity. Mutant botulinum neurotoxin B containing E1191M/S1199Y exhibits similar to 11-fold higher efficacy in blocking neurotransmission than wild-type botulinum neurotoxin B in neurons expressing human synaptotagmin II, demonstrating that enhancing receptor binding increases the overall efficacy at functional levels. The engineered botulinum neurotoxin B provides a platform to develop therapeutic toxins with improved efficacy.

Place, publisher, year, edition, pages
2017. Vol. 8, 53
Keyword [en]
Molecular medicine, Protein design, Proteins, Recombinant protein therapy
National Category
Biological Sciences
Identifiers
URN: urn:nbn:se:su:diva-145997DOI: 10.1038/s41467-017-00064-yISI: 000404575700003OAI: oai:DiVA.org:su-145997DiVA: diva2:1136542
Available from: 2017-08-28 Created: 2017-08-28 Last updated: 2017-08-28Bibliographically approved

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CiteExportLink to record
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