Crystal structure of a catalytically active, non-toxic endopeptidase derivative of Clostridium botulinum toxin A.
Botulinum neurotoxins (BoNTs) modulate cholinergic nerve terminals to result in neurotransmitter blockade. BoNTs consists of catalytic (LC), translocation (Hn) and cell-binding domains (Hc). The binding function of the Hc domain is essential for BoNTs to bind the neuronal cell membrane, therefore, removal of the Hc domain results in a product that retains the endopeptidase activity of the LC but is non-toxic. Thus, a molecule consisting of LC and Hn domains of BoNTs, termed LHn, is a suitable molecule for engineering novel therapeutics. The structure of LHA at 2.6 A reported here provides an understanding of the structural implications and challenges of engineering therapeutic molecules that combine functional properties of LHn of BoNTs with specific ligand partners to target different cell types.
Department of Biology and Biochemistry, University of Bath, Claverton Down, Bath BA2 7AY, UK.
Geoffrey
G
Masuyer
Nethaji
N
Thiyagarajan
Peter L
PL
James
Philip M H
PM
Marks
John A
JA
Chaddock
K Ravi
KR
Acharya
D019274:Botulinum Toxins, Type A / Q000737:chemistry* / Q000235:genetics / Q000633:toxicity; D002384:Catalysis; D018678:Cholinergic Agents / Q000737:chemistry* / Q000633:toxicity; D018360:Crystallography, X-Ray; D010450:Endopeptidases / Q000737:chemistry* / Q000235:genetics / Q000633:toxicity; D015202:Protein Engineering; D055550:Protein Stability; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D050825:Synaptosomal-Associated Protein 25 / Q000737:chemistry
D018678:Cholinergic Agents; D050825:Synaptosomal-Associated Protein 25; D010450:Endopeptidases; D019274:Botulinum Toxins, Type A