Abstract
Backgroundα-Conotoxins have exciting therapeutic potential based on their high selectivity and affinity for nicotinic acetylcholine receptors. The spacing between the cysteine residues in α-conotoxins is variable, leading to the classification of sub-families. BuIA is the only α-conotoxin containing a 4/4 cysteine spacing and thus it is of significant interest to examine the structure of this conotoxin.ResultsIn the current study we show the native globular disulfide connectivity of BuIA displays multiple conformations in solution whereas the non-native ribbon isomer has a single well-defined conformation. Despite having multiple conformations in solution the globular form of BuIA displays activity at the nicotinic acetylcholine receptor, contrasting with the lack of activity of the structurally well-defined ribbon isomer.ConclusionThese findings are opposite to the general trends observed for α-conotoxins where the native isomers have well-defined structures and the ribbon isomers are generally disordered. This study thus highlights the influence of the disulfide connectivity of BuIA on the dynamics of the three-dimensional structure.
Highlights
Nicotinic acetylcholine receptors play a key role in the central and peripheral nervous system and are involved in neuronal growth and plasticity, development, learning, memory and pain sensation [1,2,3,4,5]. α-Conotoxins, found in the venoms of marine molluscs belonging to the genus Conus, act as antagonists at nAChRs and have a range of potential therapeutic applications [6,7,8].Members of the α-conotoxin family inhibit either muscle, neuronal or both types of nAChRs and prevent channel opening [6,9,10]
Purification via high performance liquid chromatography (HPLC) yielded a single product for each isomer whose mass was determined using electrospray ionization mass spectrometry
HPLC traces for the purified products are shown in Fig. 1B, from which it is clear that the ribbon form elutes earlier than the globular form, indicating that its hydrophobic residues are buried to a greater extent
Summary
Members of the α-conotoxin family inhibit either muscle, neuronal or both types of nAChRs and prevent channel opening [6,9,10]. They comprise 12 to 19 amino acids, including four highly conserved cysteine residues that (page number not for citation purposes). Native α-conotoxins have a disulfide connectivity linking the first and the third, and the second and the fourth cysteine residues (CysI–CysIII and CysII–CysIV), which is referred to as the "globular" isomer.
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