5BQN

Crystal structure of the LHn fragment of botulinum neurotoxin type D, mutant H233Y E230Q

Summary for 5BQN

• Entry DOI: 10.2210/pdb5bqn/pdb
• Descriptor: Botulinum neurotoxin type D,Botulinum neurotoxin type D, 4-(2-HYDROXYETHYL)-1-PIPERAZINE ETHANESULFONIC ACID (3 entities in total)
• Functional Keywords: botulinum neurotoxin, targeted secretion inhibitors, endopeptidase, type d, protein engineering, hydrolase
• Biological source: Clostridium botulinum; More
• Cellular location: Botulinum neurotoxin D light chain: Secreted. Botulinum neurotoxin D heavy chain: Secreted: P19321
• Total number of polymer chains: 1
• Total formula weight: 102093.90

Authors

Masuyer, G.,Davies, J.R.,Moore, K.,Chaddock, J.A.,Acharya, K.R. (deposition date: 2015-05-29, release date: 2015-08-19, Last modification date: 2024-11-20)

Primary citation

Masuyer, G.,Davies, J.R.,Moore, K.,Chaddock, J.A.,Ravi Acharya, K.
Structural analysis of Clostridium botulinum neurotoxin type D as a platform for the development of targeted secretion inhibitors.
Sci Rep, 5:13397-13397, 2015

PubMed Abstract: The botulinum neurotoxin type D is one of seven highly potent toxins produced by Clostridium botulinum which inhibit neurotransmission at cholinergic nerve terminals. A functional fragment derived from the toxin, LHn, consisting of the catalytic and translocation domains, has been heralded as a platform for the development of targeted secretion inhibitors. These secretion inhibitors are aimed at retargeting the toxin towards a specific cell type to inhibit vesicular secretion. Here we report crystal structures of LHn from serotype D at 2.3 Å, and that of SXN101959 at 3.1 Å resolution. SXN101959, a derivative that combines LHn from serotype D with a fragment of the growth hormone releasing hormone, has previously revealed promising results in inhibiting growth hormone release in pituitary somatotrophs. These structures offer for the first time insights into the translocation domain interaction with the catalytic domain in serotype D. Furthermore, structural information from small-angle X-ray scattering of LHn/D is compared among serotypes A, B, and D. Taken together, these results demonstrate the robustness of the 'LHn fold' across serotypes and its use in engineering additional polypeptide components with added functionality. Our study demonstrates the suitability of botulinum neurotoxin, and serotype D in particular, as a basis for engineering novel secretion inhibitors.

PubMed: 26324071
DOI: 10.1038/srep13397

Experimental method

X-RAY DIFFRACTION (2.3 Å)