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Structural analysis of Clostridium botulinum neurotoxin type D as a platform for the development of targeted secretion inhibitors

DOI: 10.1038/srep13397 DOI Help
PMID: 26324071 PMID Help

Authors: Geoffrey Masuyer (Stockholm University) , Jonathan R. Davies (University of Bath) , Kevin Moore (Ipsen Bioinnovation Limited) , John A. Chaddock (Ipsen Bioinnovation Limited) , K. Ravi Acharya (University of Bath)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Scientific Reports , VOL 5 (13397)

State: Published (Approved)
Published: September 2015
Diamond Proposal Number(s): 8922

Open Access Open Access

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.

Subject Areas: Biology and Bio-materials

Instruments: I03-Macromolecular Crystallography

Other Facilities: DESY

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