7uie
Crystal structure of HcE-JLE-G6
Structural highlights
FunctionBXE_CLOBO Botulinum toxin acts by inhibiting neurotransmitter release. It binds to peripheral neuronal synapses, is internalized and moves by retrograde transport up the axon into the spinal cord where it can move between postsynaptic and presynaptic neurons. It inhibits neurotransmitter release by acting as a zinc endopeptidase that catalyzes the hydrolysis of the 180-Arg-|-Ile-181 bond in SNAP-25. Publication Abstract from PubMedBotulinum neurotoxin E (BoNT/E) is one of the major causes of human botulism and paradoxically also a promising therapeutic agent. Here we determined the co-crystal structures of the receptor-binding domain of BoNT/E (H(C)E) in complex with its neuronal receptor synaptic vesicle glycoprotein 2A (SV2A) and a nanobody that serves as a ganglioside surrogate. These structures reveal that the protein-protein interactions between H(C)E and SV2 provide the crucial location and specificity information for H(C)E to recognize SV2A and SV2B, but not the closely related SV2C. At the same time, H(C)E exploits a separated sialic acid-binding pocket to mediate recognition of an N-glycan of SV2. Structure-based mutagenesis and functional studies demonstrate that both the protein-protein and protein-glycan associations are essential for SV2A-mediated cell entry of BoNT/E and for its potent neurotoxicity. Our studies establish the structural basis to understand the receptor-specificity of BoNT/E and to engineer BoNT/E variants for new clinical applications. Structural basis for botulinum neurotoxin E recognition of synaptic vesicle protein 2.,Liu Z, Lee PG, Krez N, Lam KH, Liu H, Przykopanski A, Chen P, Yao G, Zhang S, Tremblay JM, Perry K, Shoemaker CB, Rummel A, Dong M, Jin R Nat Commun. 2023 Apr 24;14(1):2338. doi: 10.1038/s41467-023-37860-8. PMID:37095076[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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