6ZVN

Botulinum neurotoxin B2 binding domain in complex with human synaptotagmin I

This is a non-PDB format compatible entry.

Summary for 6ZVN

• Entry DOI: 10.2210/pdb6zvn/pdb
• Descriptor: Neurotoxin, Synaptotagmin-1 (3 entities in total)
• Functional Keywords: botulinum neurotoxin, ganglioside, gt1b, bont, b2, toxin
• Biological source: Clostridium botulinum; More
• Total number of polymer chains: 2
• Total formula weight: 54936.72

Authors

Davies, J.R.,Masuyer, G.,Stenmark, P. (deposition date: 2020-07-25, release date: 2020-10-14, Last modification date: 2024-01-31)

Primary citation

Davies, J.R.,Masuyer, G.,Stenmark, P.
Structural and Biochemical Characterization of Botulinum Neurotoxin Subtype B2 Binding to Its Receptors.
Toxins, 12:-, 2020

PubMed Abstract: 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, …). 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 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.

PubMed: 32957706
DOI: 10.3390/toxins12090603

Experimental method

X-RAY DIFFRACTION (2.5 Å)