Membrane-mediated interaction of non-conventional snake three-finger toxins with nicotinic acetylcholine receptors

Nicotinic acetylcholine receptor of alpha 7 type (alpha 7-nAChR) presented in the nervous and immune systems and epithelium is a promising therapeutic target for cognitive disfunctions and cancer treatment. Weak toxin from Naja kaouthia venom (WTX) is a non-conventional three-finger neurotoxin, targeting alpha 7-nAChR with weak affinity. There are no data on interaction mode of non-conventional neurotoxins with nAChRs. Using alpha-bungarotoxin (classical three-finger neurotoxin with high affinity to alpha 7-nAChR), we showed applicability of cryo-EM to study complexes of alpha 7-nAChR extracellular ligand-binding domain (alpha 7-ECD) with toxins. Using cryo-EM structure of the alpha 7-ECD/WTX complex, together with NMR data on membrane active site in the WTX molecule and mutagenesis data, we reconstruct the structure of alpha 7-nAChR/WTX complex in the membrane environment. WTX interacts at the entrance to the orthosteric site located at the receptor intersubunit interface and simultaneously forms the contacts with the membrane surface. WTX interaction mode with alpha 7-nAChR significantly differs from alpha-bungarotoxin's one, which does not contact the membrane. Our study reveals the important role of the membrane for interaction of non-conventional neurotoxins with the nicotinic receptors.

Automated summary

The alpha 7-nAChR is a potential therapeutic target for cognitive dysfunction and cancer treatment. WTX, a non-conventional neurotoxin, shows weak affinity to the alpha 7-nAChR. Our study reveals significant differences in the interaction mode between non-conventional neurotoxins and nicotinic receptors compared to classical neurotoxins, emphasizing the importance of the membrane for their interaction.