9ea9
From Proteopedia
Crystal structure of BoNT/A-NTNH-HA70 -VHH_F12-VHH_H7-Fab_NTNH complex
Structural highlights
FunctionBXA1_CLOBO Inhibits acetylcholine release. The botulinum toxin binds with high affinity to peripheral neuronal presynaptic membrane to the secretory vesicle protein SV2. It binds directly to the largest luminal loop of SV2A, SV2B and SV2C. It is then internalized by receptor-mediated endocytosis. The C-terminus of the heavy chain (H) is responsible for the adherence of the toxin to the cell surface while the N-terminus mediates transport of the light chain from the endocytic vesicle to the cytosol. After translocation, the light chain (L) hydrolyzes the 197-Gln-|-Arg-198 bond in SNAP-25, thereby blocking neurotransmitter release. Inhibition of acetylcholine release results in flaccid paralysis, with frequent heart or respiratory failure. Publication Abstract from PubMedBotulinum neurotoxin serotype A (BoNT/A) is naturally produced by bacteria along with four nontoxic neurotoxin-associated proteins (NTNH, HA70, HA33, and HA17), forming a bimodular large progenitor toxin complex (L-PTC). The BoNT/A-NTNH complex protects the toxin from adverse environment, while the complex consisting of HA proteins facilitates toxin absorption during oral intoxication. How these two independent modules assemble into the L-PTC remains unclear. Here, we report the crystal structure of the BoNT/A-NTNH-HA70 complex at ~2.9-A resolution. The structure reveals that the BoNT/A-NTNH complex is anchored into a concentric double beta-barrel channel of trimeric HA70 through a short beta-hairpin of NTNH (termed nLoop), resembling a nut-and-bolt attachment. We find that the nLoop of NTNH is strictly conserved across HA-containing BoNT complexes and that NTNH-HA70 binding is interchangeable among them. Furthermore, we demonstrate that the nLoop functions as a minimal motif enabling attachment of a protein-of-interest to the HA complex, with potential applications in oral biologics delivery. A nut-and-bolt assembly of the bimodular large progenitor botulinum neurotoxin complex.,Lam KH, Gao L, Przykopanski A, Chen B, Huang T, Kruger M, Bartels AM, Dorner MB, Perry K, Dorner BG, Rummel A, Jin R Sci Adv. 2025 Aug 29;11(35):eadx5831. doi: 10.1126/sciadv.adx5831. Epub 2025 Aug , 27. PMID:40864694[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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