NMR structure determination of alpha-conotoxin BuIA, a novel neuronal nicotinic acetylcholine receptor antagonist with an unusual 4/4 disulfide scaffold.
We have determined a high-resolution three-dimensional structure of alpha-conotoxin BuIA, a 13-residue peptide toxin isolated from Conus bullatus. Despite its unusual 4/4 disulfide bond layout alpha-conotoxin BuIA exhibits strong antagonistic activity at alpha6/alpha3beta2beta3, alpha3beta2, and alpha3beta4 nAChR subtypes like some alpha4/7 conotoxins. alpha-Conotoxin BuIA lacks the C-terminal beta-turn present within the second disulfide loop of alpha4/7 conotoxins, having only a "pseudo omega-shaped" molecular topology. Nevertheless, it contains a functionally critical two-turn helix motif, a feature ubiquitously found in alpha4/7 conotoxins. Such an aspect seems mainly responsible for similarities in the receptor recognition profile of alpha-conotoxin BuIA to alpha4/7 conotoxins. Structural comparison of alpha-conotoxin BuIA with alpha4/7 conotoxins and alpha4/3 conotoxin ImI suggests that presence of the second helical turn portion of the two-turn helix motif in alpha4/7 and alpha4/4 conotoxins may be important for binding to the alpha3 and/or alpha6 subunit of nAChR.
Chi
Seung-Wook
SW
Molecular Cancer Research Center, Division of Molecular Therapeutics, KRIBB, Daejeon 305-806, Republic of Korea.
Kim
Do-Hyoung
DH
Olivera
Baldomero M
BM
McIntosh
J Michael
JM
Han
Kyou-Hoon
KH
D000818:Animals; D001665:Binding Sites; D003198:Computer Simulation; D020916:Conotoxins / Q000032:analysis / Q000737:chemistry*; D052078:Conus Snail / Q000378:metabolism*; D003461:Crystallography; D004220:Disulfides; D009682:Magnetic Resonance Spectroscopy; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation; D018733:Nicotinic Antagonists / Q000737:chemistry*; D011485:Protein Binding; D011978:Receptors, Nicotinic / Q000737:chemistry
D020916:Conotoxins; D004220:Disulfides; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; C515221:alpha-conotoxin BuIA, Conus bullatus