Harnessing snake venom cardiotoxins for antimicrobial peptide discovery

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  Harnessing snake venom cardiotoxins for antimicrobial peptide discovery Abstract Snake venoms are a rich source of bioactive molecules with considerable potential for drug discovery. Cardiotoxins (CTXs) from cobras ( Naja spp.) are membrane-active venom proteins and promising templates for antimicrobial peptide development. Here, we combined two computational toxin-mining strategies to identify antimicrobial peptide candidates from CTXs. First, AMPA-guided sequence mining was used to detect encrypted antimicrobial regions within CTX sequences. Second, sequence alignment and consensus-sequence analysis were employed to generate peptides from a conserved CTX scaffold. Candidate peptides were prioritised using multiple machine learning- and deep learning-based antimicrobial peptide prediction tools, resulting in fourteen CTX-inspired peptides, including two modified derivatives of CTX-p5. Antimicrobial screening showed limited activity across the peptide panel, with CTX-p5 exhibiti...

Molecular mechanism of α-latrotoxin action

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Molecular mechanism of α-latrotoxin action

Abstract


The potent neurotoxic venom of the black widow spider contains a cocktail of seven phylum-specific latrotoxins (LTXs), but only one, α-LTX, targets vertebrates. This 130 kDa toxin binds to receptors at presynaptic nerve terminals and triggers a massive release of neurotransmitters. It is widely accepted that LTXs tetramerize and insert into the presynaptic membrane, thereby forming Ca2+-conductive pores, but the underlying mechanism remains poorly understood. LTXs are homologous and consist of an N-terminal region with three distinct domains, along with a C-terminal domain containing up to 22 consecutive ankyrin repeats. Here we report the first high resolution structures of the vertebrate-specific α-LTX tetramer in its prepore and pore state. Our structures, in combination with AlphaFold2-based structural modeling and molecular dynamics simulations, reveal dramatic conformational changes in the N-terminal region of the complex. Four distinct helical bundles synchronously rearrange to progressively form a highly stable 15 nm cation-impermeable coiled-coil stalk. This stalk, in turn, positions an N-terminal pair of helices within the membrane, thereby enabling the assembly of a cation-permeable channel. Taken together, these data unveil a unique mechanism for membrane insertion and channel formation, characteristic of the LTX family, and provide the necessary framework for advancing novel therapeutics and biotechnological applications.


Molecular mechanism of α-latrotoxin action Bjoern Udo Klink, Azadeh Alavizargar, Kalyankumar Karthik Subramaniam, Minghao Chen, Andreas Heuer, Christos Gatsogiannis
bioRxiv 2024.03.06.583760; doi: https://doi.org/10.1101/2024.03.06.583760