Structure of alpha-conotoxin BuIA: influences of disulfide connectivity on structural dynamics.
BACKGROUND
Alpha-conotoxins have exciting therapeutic potential based on their high selectivity and affinity for nicotinic acetylcholine receptors. The spacing between the cysteine residues in alpha-conotoxins is variable, leading to the classification of sub-families. BuIA is the only alpha-conotoxin containing a 4/4 cysteine spacing and thus it is of significant interest to examine the structure of this conotoxin.


RESULTS
In 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.


CONCLUSIONS
These findings are opposite to the general trends observed for alpha-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.
Jin
Ai-Hua
AH
Institute for Molecular Bioscience, Australian Research Council Special Research Centre for Functional and Applied Genomics, The University of Queensland, Brisbane QLD, Australia. a.jin@imb.uq.edu.au <a.jin@imb.uq.edu.au>
Brandstaetter
Hemma
H
Nevin
Simon T
ST
Tan
Chia Chia
CC
Clark
Richard J
RJ
Adams
David J
DJ
Alewood
Paul F
PF
Craik
David J
DJ
Daly
Norelle L
NL
D000595:Amino Acid Sequence; D000818:Animals; D020916:Conotoxins / Q000737:chemistry* / Q000378:metabolism*; D004220:Disulfides / Q000737:chemistry* / Q000378:metabolism*; D004594:Electrophysiology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D009865:Oocytes; D018408:Patch-Clamp Techniques; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011978:Receptors, Nicotinic / Q000737:chemistry / Q000378:metabolism; D014981:Xenopus
D020916:Conotoxins; D004220:Disulfides; D020033:Protein Isoforms; D011978:Receptors, Nicotinic