6BVD

Structure of Botulinum Neurotoxin Serotype HA Light Chain

6BVD の概要

• エントリーDOI: 10.2210/pdb6bvd/pdb
• 分子名称: Light Chain, CALCIUM ION, ACETATE ION, ... (5 entities in total)
• 機能のキーワード: toxin, metalloendopeptidase, proteolysis
• 由来する生物種: Clostridium botulinum
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 99679.23

構造登録者

Jin, R.,Lam, K. (登録日: 2017-12-12, 公開日: 2018-05-09, 最終更新日: 2023-10-04)

主引用文献

Lam, K.H.,Sikorra, S.,Weisemann, J.,Maatsch, H.,Perry, K.,Rummel, A.,Binz, T.,Jin, R.
Structural and biochemical characterization of the protease domain of the mosaic botulinum neurotoxin type HA.
Pathog Dis, 76:-, 2018

PubMed Abstract: The extreme toxicity of botulinum neurotoxins (BoNTs) relies on their specific cleavage of SNARE proteins, which eventually leads to muscle paralysis. One newly identified mosaic toxin, BoNT/HA (aka H or FA), cleaves VAMP-2 at a unique position between residues L54 and E55, but the molecular basis underlying VAMP-2 recognition of BoNT/HA remains poorly characterized. Here, we report a ∼2.09 Å resolution crystal structure of the light chain protease domain of BoNT/HA (LC/HA). Structural comparison between LC/HA and LC of BoNT/F1 (LC/F1) reveals distinctive hydrophobic and electrostatic features near the active sites, which may explain their different VAMP-2 cleavage sites. When compared to BoNT/F5 that cleaves VAMP-2 at the same site as BoNT/HA, LC/HA displays higher affinity for VAMP-2, which could be caused by their different surface charge properties surrounding a VAMP-2 exosite-binding cleft. Furthermore, systematic mutagenesis studies on VAMP-2 and structural modeling demonstrate that residues R47 to K59 spanning the cleavage site in VAMP-2 may adopt a novel extended conformation when interacting with LC/HA and LC/F5. Taken together, our structure provides new insights into substrate recognition of BoNT/HA and paves the way for rational design of small molecule or peptide inhibitors against LC/HA.

PubMed: 29688327
DOI: 10.1093/femspd/fty044

実験手法

X-RAY DIFFRACTION (2.09 Å)