7T5F

Botulinum neurotoxin Type B Light Chain complexed with nanobodies JLJ-G3 and JNE-B10

7T5F の概要

• エントリーDOI: 10.2210/pdb7t5f/pdb
• 分子名称: Botulinum neurotoxin type B, JLJ-G3, JNE-B10, ... (6 entities in total)
• 機能のキーワード: botulinum neurotoxin, camelid heavy chain antibody, endopeptidase, inhibitor, toxin
• 由来する生物種: Clostridium botulinum; 詳細
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 156089.62

構造登録者

Jin, R.,Lam, K.-H. (登録日: 2021-12-12, 公開日: 2021-12-29, 最終更新日: 2024-10-30)

主引用文献

Lam, K.H.,Tremblay, J.M.,Perry, K.,Ichtchenko, K.,Shoemaker, C.B.,Jin, R.
Probing the structure and function of the protease domain of botulinum neurotoxins using single-domain antibodies.
Plos Pathog., 18:e1010169-e1010169, 2022

PubMed Abstract: Botulinum neurotoxins (BoNTs) are among the deadliest of bacterial toxins. BoNT serotype A and B in particular pose the most serious threat to humans because of their high potency and persistence. To date, there is no effective treatment for late post-exposure therapy of botulism patients. Here, we aim to develop single-domain variable heavy-chain (VHH) antibodies targeting the protease domains (also known as the light chain, LC) of BoNT/A and BoNT/B as antidotes for post-intoxication treatments. Using a combination of X-ray crystallography and biochemical assays, we investigated the structures and inhibition mechanisms of a dozen unique VHHs that recognize four and three non-overlapping epitopes on the LC of BoNT/A and BoNT/B, respectively. We show that the VHHs that inhibit the LC activity occupy the extended substrate-recognition exosites or the cleavage pocket of LC/A or LC/B and thus block substrate binding. Notably, we identified several VHHs that recognize highly conserved epitopes across BoNT/A or BoNT/B subtypes, suggesting that these VHHs exhibit broad subtype efficacy. Further, we identify two novel conformations of the full-length LC/A, that could aid future development of inhibitors against BoNT/A. Our studies lay the foundation for structure-based engineering of protein- or peptide-based BoNT inhibitors with enhanced potencies and cross-subtypes properties.

PubMed: 34990480
DOI: 10.1371/journal.ppat.1010169

実験手法

X-RAY DIFFRACTION (2.6 Å)