6G5F

Crystal structure of an engineered Botulinum Neurotoxin type B mutant E1191M/S1199Y in complex with human synaptotagmin 1

6G5F の概要

• エントリーDOI: 10.2210/pdb6g5f/pdb
• 分子名称: Botulinum neurotoxin type B, Synaptotagmin-1, GLYCEROL, ... (5 entities in total)
• 機能のキーワード: botulinum toxin, neurotoxin, protein engineering, receptor binding, toxin
• 由来する生物種: Clostridium botulinum; 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 304983.75

構造登録者

Masuyer, G.,Elliot, M.,Favre-Guilmard, C.,Liu, S.M.,Maignel, J.,Beard, M.,Carre, D.,Kalinichev, M.,Lezmi, S.,Mir, I.,Nicoleau, C.,Palan, S.,Perier, C.,Raban, E.,Dong, M.,Krupp, J.,Stenmark, P. (登録日: 2018-03-29, 公開日: 2019-01-16, 最終更新日: 2024-11-13)

主引用文献

Elliott, M.,Favre-Guilmard, C.,Liu, S.M.,Maignel, J.,Masuyer, G.,Beard, M.,Boone, C.,Carre, D.,Kalinichev, M.,Lezmi, S.,Mir, I.,Nicoleau, C.,Palan, S.,Perier, C.,Raban, E.,Zhang, S.,Dong, M.,Stenmark, P.,Krupp, J.
Engineered botulinum neurotoxin B with improved binding to human receptors has enhanced efficacy in preclinical models.
Sci Adv, 5:eaau7196-eaau7196, 2019

PubMed Abstract: Although botulinum neurotoxin serotype A (BoNT/A) products are common treatments for various disorders, there is only one commercial BoNT/B product, whose low potency, likely stemming from low affinity toward its human receptor synaptotagmin 2 (hSyt2), has limited its therapeutic usefulness. We express and characterize two full-length recombinant BoNT/B1 proteins containing designed mutations E1191M/S1199Y (rBoNT/B1) and E1191Q/S1199W (rBoNT/B1) that enhance binding to hSyt2. In preclinical models including human-induced pluripotent stem cell neurons and a humanized transgenic mouse, this increased hSyt2 affinity results in high potency, comparable to that of BoNT/A. Last, we solve the cocrystal structure of rBoNT/B1 in complex with peptides of hSyt2 and its homolog hSyt1. We demonstrate that neuronal surface receptor binding limits the clinical efficacy of unmodified BoNT/B and that modified BoNT/B proteins have promising clinical potential.

PubMed: 30746458
DOI: 10.1126/sciadv.aau7196

実験手法

X-RAY DIFFRACTION (2.5 Å)