6uc6

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Crystal structure of BoNT/B receptor-binding domain in complex with VHH JLI-H11

Structural highlights

6uc6 is a 4 chain structure with sequence from Clostridium botulinum and Vicugna pacos. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.3200588Å
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

BXB_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 cleaves the '76-Gln-|-Phe-77' bond of synaptobrevin-2.

Publication Abstract from PubMed

Botulinum neurotoxin (BoNT) is one of the most acutely lethal toxins known to humans, and effective treatment for BoNT intoxication is urgently needed. Single-domain antibodies (VHH) have been examined as a countermeasure for BoNT because of their high stability and ease of production. Here, we investigate the structures and the neutralization mechanisms for six unique VHHs targeting BoNT/A1 or BoNT/B1. These studies reveal diverse neutralizing mechanisms by which VHHs prevent host receptor binding or block transmembrane delivery of the BoNT protease domain. Guided by this knowledge, we design heterodimeric VHHs by connecting two neutralizing VHHs via a flexible spacer so they can bind simultaneously to the toxin. These bifunctional VHHs display much greater potency in a mouse co-intoxication model than similar heterodimers unable to bind simultaneously. Taken together, our studies offer insight into antibody neutralization of BoNTs and advance our ability to design multivalent anti-pathogen VHHs with improved therapeutic properties.

Structural Insights into Rational Design of Single-Domain Antibody-Based Antitoxins against Botulinum Neurotoxins.,Lam KH, Tremblay JM, Vazquez-Cintron E, Perry K, Ondeck C, Webb RP, McNutt PM, Shoemaker CB, Jin R Cell Rep. 2020 Feb 25;30(8):2526-2539.e6. doi: 10.1016/j.celrep.2020.01.107. PMID:32101733^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Lam KH, Tremblay JM, Vazquez-Cintron E, Perry K, Ondeck C, Webb RP, McNutt PM, Shoemaker CB, Jin R. Structural Insights into Rational Design of Single-Domain Antibody-Based Antitoxins against Botulinum Neurotoxins. Cell Rep. 2020 Feb 25;30(8):2526-2539.e6. PMID:32101733 doi:10.1016/j.celrep.2020.01.107