Title : Crystal
structure of the BoNT /A2 receptor-binding
domain in complex with the luminal
domain of its neuronal receptor
SV2C
Abstract :
- A detailed molecular understanding of botulinum neurotoxin (BoNT) BoNT )/host-cell-receptor interactions is fundamental both for developing strategies against botulism and for generating improved BoNT variants for medical applications
- The X-ray crystal structure of the receptor-binding domain (HC) of BoNT /A1 in complex with the luminal domain (LD) of its neuronal receptor SV2C revealed only few specific side-chain - side-chain interactions that are important for binding
- Notably, two BoNT /A1 residues, Arg 1156 and Arg 1294 , that are crucial for the interaction with SV2 , are not conserved among subtypes
- Because it has been suggested that differential receptor binding of subtypes might explain their differences in biological activity, we determined the crystal structure of BoNT /A2-HC in complex with SV2C-LD
- Although only few side-chain interactions are conserved between the two BoNT /A subtypes, the overall binding mode of subtypes A1 and A2 is virtually identical
- In the BoNT/A2-HC - SV2C complex structure , a missing cation-π stacking is compensated for by an additional salt bridge and an anion-π stacking interaction, which explains why the binding of BoNT /A subtypes to SV2C tolerates variable side chains
- These findings suggest that motif extensions and a shallow binding cleft in BoNT / A-HC contribute to binding specificity