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Engineered botulinu...
Engineered botulinum neurotoxin B with improved efficacy for targeting human receptors
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Tao, Liang (author)
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Peng, Lisheng (author)
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- Berntsson, Ronnie P. -A. (author)
- Umeå universitet,Stockholms universitet,Institutionen för biokemi och biofysik,Umeå University, Sweden,Institutionen för medicinsk kemi och biofysik,Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden
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Liu, Sai Man (author)
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Park, SunHyun (author)
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Yu, Feifan (author)
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Boone, Christopher (author)
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Palan, Shilpa (author)
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Beard, Matthew (author)
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Chabrier, Pierre-Etienne (author)
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- Stenmark, Pål (author)
- Stockholms universitet,Institutionen för biokemi och biofysik
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Krupp, Johannes (author)
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Dong, Min (author)
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(creator_code:org_t)
- 2017-07-03
- 2017
- English.
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8
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https://umu.diva-por... (primary) (Raw object)
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Abstract
Subject headings
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- 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.
Subject headings
- NATURVETENSKAP -- Biologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinsk bioteknologi -- Medicinsk bioteknologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Medical Biotechnology -- Medical Biotechnology (hsv//eng)
Keyword
- Molecular medicine
- Protein design
- Proteins
- Recombinant protein therapy
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Tao, Liang
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Peng, Lisheng
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Berntsson, Ronni ...
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Liu, Sai Man
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Park, SunHyun
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Yu, Feifan
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show more...
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Boone, Christoph ...
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Palan, Shilpa
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Beard, Matthew
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Chabrier, Pierre ...
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Stenmark, Pål
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Krupp, Johannes
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Dong, Min
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show less...
- About the subject
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- NATURAL SCIENCES
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NATURAL SCIENCES
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and Biological Scien ...
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Medical Biotechn ...
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and Medical Biotechn ...
- Articles in the publication
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Nature Communica ...
- By the university
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Stockholm University
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Umeå University