Elucidation of critical pH-dependent structural changes in Botulinum Neurotoxin E |
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| Affiliation: | 1. Department of Biochemical Engineering, Bernard Katz Building, University College London, Gordon Street, London WC1H 0AH, UK;2. Evox Therapeutics Ltd, Oxford Science Park, Medwar Center, Oxford, England OX4 4HG, UK;3. FairJourney Biologics, 823 Rua do Campo Alegre, Porto, Porto 4150-180, Portugal;4. Ipsen Bioinnovation, 102 Park Drive, Milton Park, Abingdon, Oxfordshire OX14 4RY UK;5. Ipsen Biopharm Ltd., Wrexham Industrial Estate, 9 Ash Road, LL13 9UF, UK;6. UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London WC1N 1AX, UK;7. Department of Structural and Molecular Biology, Division of Biosciences, Darwin Building, University College London, Gower Street, London WC1E 6BT, UK |
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| Abstract: | Botulinum Neurotoxins (BoNT) are the most potent toxins currently known. However, they also have therapeutic applications for an increasing number of motor related conditions due to their specificity, and low diffusion into the system. Although the start- and end- points for the BoNT mechanism of action are well-studied, a critical step remains poorly understood. It is theorised that BoNTs undergo a pH-triggered conformational shift, activating the neurotoxin by priming it to form a transmembrane (TM) channel. To test this hypothesis, we combined molecular dynamics (MD) simulations and small-angle x-ray scattering (SAXS), revealing a new conformation of serotype E (BoNT/E). This conformation was exclusively observed in simulations below pH 5.5, as determined by principal component analysis (PCA), and its theoretical SAXS profile matched an experimental SAXS profile obtained at pH 4. Additionally, a localised secondary structural change was observed in MD simulations below pH 5.5, in a region previously identified as instrumental for membrane insertion for serotype A (BoNT/A). These changes were found at a critical pH value for BoNTs in vivo, and may be relevant for their therapeutic use. |
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| Keywords: | Botulinum Neurotoxin Molecular dynamics Small-angle X-ray scattering MD" },{" #name" :" keyword" ," $" :{" id" :" pc_wXi33HQmwV" }," $$" :[{" #name" :" text" ," _" :" Molecular Dynamics SAXS" },{" #name" :" keyword" ," $" :{" id" :" pc_P5YsYkyJao" }," $$" :[{" #name" :" text" ," _" :" Small Angle X-ray Scattering BoNT/E" },{" #name" :" keyword" ," $" :{" id" :" pc_FHlqqLWW2r" }," $$" :[{" #name" :" text" ," _" :" Botulinum Neurotoxin - serotype E LD50" },{" #name" :" keyword" ," $" :{" id" :" pc_LM4vJP0u6m" }," $$" :[{" #name" :" text" ," _" :" Lethal dose 50% RMSD" },{" #name" :" keyword" ," $" :{" id" :" pc_Ss17vL7CQ9" }," $$" :[{" #name" :" text" ," _" :" Root mean square deviation SASA" },{" #name" :" keyword" ," $" :{" id" :" pc_na0I3OOXxg" }," $$" :[{" #name" :" text" ," _" :" Solvent Accessible Surface Area BoNT/A" },{" #name" :" keyword" ," $" :{" id" :" pc_wjGMuMnlZg" }," $$" :[{" #name" :" text" ," _" :" Botulinum Neurotoxin - serotype A |
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