{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T03:16:41Z","timestamp":1760239001868,"version":"build-2065373602"},"reference-count":42,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2020,9,17]],"date-time":"2020-09-17T00:00:00Z","timestamp":1600300800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004359","name":"Vetenskapsr\u00e5det","doi-asserted-by":"publisher","award":["2018-03406"],"award-info":[{"award-number":["2018-03406"]}],"id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002794","name":"Cancerfonden","doi-asserted-by":"publisher","award":["CAN 2017\/716"],"award-info":[{"award-number":["CAN 2017\/716"]}],"id":[{"id":"10.13039\/501100002794","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxins"],"abstract":"<jats:p>Botulinum neurotoxins (BoNTs) can be used therapeutically to treat a wide range of neuromuscular and neurological conditions. A collection of natural BoNT variants exists which can be classified into serologically distinct serotypes (BoNT\/B), and further divided into subtypes (BoNT\/B1, B2, \u2026). BoNT subtypes share a high degree of sequence identity within the same serotype yet can display large variation in toxicity. One such example is BoNT\/B2, which was isolated from Clostridium botulinum strain 111 in a clinical case of botulism, and presents a 10-fold lower toxicity than BoNT\/B1. In an effort to understand the molecular mechanisms behind this difference in potency, we here present the crystal structures of BoNT\/B2 in complex with the ganglioside receptor GD1a, and with the human synaptotagmin I protein receptor. We show, using receptor-binding assays, that BoNT\/B2 has a slightly higher affinity for GD1a than BoNT\/B1, and confirm its considerably weaker affinity for its protein receptors. Although the overall receptor-binding mechanism is conserved for both receptors, structural analysis suggests the lower affinity of BoNT\/B2 is the result of key substitutions, where hydrophobic interactions important for synaptotagmin-binding are replaced by polar residues. This study provides a template to drive the development of future BoNT therapeutic molecules centered on assessing the natural subtype variations in receptor-binding that appears to be one of the principal stages driving toxicity.<\/jats:p>","DOI":"10.3390\/toxins12090603","type":"journal-article","created":{"date-parts":[[2020,9,18]],"date-time":"2020-09-18T10:22:23Z","timestamp":1600424543000},"page":"603","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Structural and Biochemical Characterization of Botulinum Neurotoxin Subtype B2 Binding to Its Receptors"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4986-8594","authenticated-orcid":false,"given":"Jonathan R.","family":"Davies","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Biophysics, Stockholm University, SE-106 91 Stockholm, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9527-2310","authenticated-orcid":false,"given":"Geoffrey","family":"Masuyer","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Biophysics, Stockholm University, SE-106 91 Stockholm, Sweden"},{"name":"Department of Pharmacy and Pharmacology, Centre for Therapeutic Innovation, University of Bath, Bath BA2 7AY, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4777-3417","authenticated-orcid":false,"given":"P\u00e5l","family":"Stenmark","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Biophysics, Stockholm University, SE-106 91 Stockholm, Sweden"},{"name":"Department of Experimental Medical Science, Lund University, SE-221 00 Lund, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,9,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1146\/annurev-biochem-013118-111654","article-title":"Botulinum and Tetanus Neurotoxins","volume":"88","author":"Dong","year":"2019","journal-title":"Annu. 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