Toxins

Toxic knottins inhibit ion channels, but the mechanism of inhibition remains unknown.

It has been shown that the spider toxin VSTX1 reaches its target by partitioning into the lipid membrane [Lee & MacKinnon, 2004].

Moreover, both the spider toxin GsMTx4, and its enantiomer, enGsMTx4, were shown to modify the gating of the target ion channel, ruling out the traditional lock-and-key model of ligand-protein interactions. It is hypothesized that GsMTx4 and enGsMTx4 alter the lipid packing at the bilayer/solution/channel interface [Suchyna et al., 2004; Garcia, 2004]. Molecular dynamics simulations have evidenced two modes of binding between GsMTx4 and membranes. A deep binding is favored when a DPPC (dipalmitoyl-phosphatidylcholine) membrane is used at 310 K, indicating that toxin binding with biological membranes is affected by the structure of the lipid acyl chains [Nishizawa & Nishizawa, 2007].

Further studies have shown however that bilayer partitioning is not a universal property of the toxic knottins that interact with ion channels [Posokhov et al., 2007].

More recently, the asteropsin A, an unusual cystine-crosslinked peptide from porifera, has been shown to induce neuronal Ca2+ influx when it was administered together with the Na+ channel activator veratridine [Li et al., 2013].

In 2016, a sodium channel inhibitor ISTX-I with a novel structure has been discovered and provides a new hint at the evolutionary link between two toxin folds [Rong et al., 2016].

Toxic Knottins are able to block many ion channels

exemples are shown below