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Toxins 2018, 10(4), 153; https://doi.org/10.3390/toxins10040153

Crystal Structure of Botulinum Neurotoxin A2 in Complex with the Human Protein Receptor SV2C Reveals Plasticity in Receptor Binding

1
Department of Biochemistry and Biophysics, Stockholm University, S-106 91 Stockholm, Sweden
2
Department of Urology, Boston Children’s Hospital, Department of Microbiology and Immunobiology and Department of Surgery, Harvard Medical School, Boston, MA 02115, USA
*
Authors to whom correspondence should be addressed.
Received: 6 March 2018 / Revised: 28 March 2018 / Accepted: 10 April 2018 / Published: 12 April 2018
(This article belongs to the Special Issue Bacterial Toxins: Structure–Function Relationship)
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Abstract

Botulinum neurotoxins (BoNTs) are a family of highly dangerous bacterial toxins, with seven major serotypes (BoNT/A-G). Members of BoNTs, BoNT/A1 and BoNT/B1, have been utilized to treat an increasing number of medical conditions. The clinical trials are ongoing for BoNT/A2, another subtype of BoNT/A, which showed promising therapeutic properties. Both BoNT/A1 and BoNT/A2 utilize three isoforms of synaptic vesicle protein SV2 (SV2A, B, and C) as their protein receptors. We here present a high resolution (2.0 Å) co-crystal structure of the BoNT/A2 receptor-binding domain in complex with the human SV2C luminal domain. The structure is similar to previously reported BoNT/A-SV2C complexes, but a shift of the receptor-binding segment in BoNT/A2 rotates SV2C in two dimensions giving insight into the dynamic behavior of the interaction. Small differences in key residues at the binding interface may influence the binding to different SV2 isoforms, which may contribute to the differences between BoNT/A1 and BoNT/A2 observed in the clinic. View Full-Text
Keywords: botulinum toxin; cell surface receptor; N-linked glycosylation; neurotoxin; protein structure; protein–protein interaction; extracellular domain; membrane protein; structural biology; X-ray crystallography botulinum toxin; cell surface receptor; N-linked glycosylation; neurotoxin; protein structure; protein–protein interaction; extracellular domain; membrane protein; structural biology; X-ray crystallography
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).
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Gustafsson, R.; Zhang, S.; Masuyer, G.; Dong, M.; Stenmark, P. Crystal Structure of Botulinum Neurotoxin A2 in Complex with the Human Protein Receptor SV2C Reveals Plasticity in Receptor Binding. Toxins 2018, 10, 153.

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