THREE-FINGER TOXINS AS SELECTIVE PROBES TO DISTINGUISH SUBUNIT INTERFACES OF NICOTINIC ACETYLCHOLINE RECEPTORS

Three-finger toxins (3FTxs) are a major family of snake toxins, containing ?-neurotoxins and ?-neurotoxins that selectively antagonize postsynaptic nicotinic acetylcholine receptors (nAChRs). For the first time, the cryo-EM structure of a natural ?-neurotoxin, Erabutoxin-A (Ea), complexed with Tetronarce californica nAChR has been elucidated. From the atomic model, in silico Ea mutants at the nAChR binding interface were used to study intramolecular selectivity between the two binding sites. These Ea mutants were also used to study intramolecular selectivity within the human muscle nAChR using dose-response curves from electrophysiological inhibition. Nicotine was also observed to selectively open human fetal muscle nAChRs over adult muscle nAChRs. To investigate intermolecular selectivity between neuronal nAChR subtypes, novel ?-neurotoxins Oh9-1 and Exactin were observed to have different inhibitory strengths for neuronal nAChRs ?7, ?3?4 and ?4?2. Using the structural and functional information of the selective neurotoxins, novel probes can be designed to study specific nAChRs.

Author dc:creator

• CHAN YUE LING, CHRISTABEL

• Three-finger toxins, nicotinic acetylcholine receptor, interface selectivity, short-chain neurotoxin, cryo-electron microscopy, electrophysiology