Conformational analysis of a toxic peptide from Trimeresurus wagleri which blocks the nicotinic acetylcholine receptor.
The 22-residue toxic peptide (WTX1) from the venom of the Southeast Asian snake Trimeresurus wagleri has multiple sites of action, but its lethal effect has been attributed to blocking the postsynaptic acetylcholine receptor at the neuromuscular junction. The 3-dimensional structure of WTX1 was studied using 2-dimensional nuclear magnetic resonance spectroscopy, circular dichroism, and computer simulations. In aqueous solution, WTX1 was shown to have extended and flexible "tails" defined by a short, rigid disulfide-bonded loop. The flexible regions can undergo structural rearrangement when moved from an aqueous to a less polar environment and may contribute to its effectiveness at different receptor sites. By substituting Gly or Phe for His at position 10, significant effects on the disulfide bond formation and, thereby, the activity of the peptide were observed. These results suggest that even subtle differences in single residues can have profound effects on the dynamics of folding, disulfide bond formation, and activity of this toxic peptide.
Sellin
L C
LC
Department of Physical Sciences, University of Oulu, Finland. lawrence@phoenix.oulu.fi
Mattila
K
K
Annila
A
A
Schmidt
J J
JJ
McArdle
J J
JJ
Hyvönen
M
M
Rantala
T T
TT
Kivistö
T
T
D000595:Amino Acid Sequence; D000818:Animals; D055592:Biophysical Phenomena; D001703:Biophysics; D002942:Circular Dichroism; D003435:Crotalid Venoms / Q000737:chemistry* / Q000235:genetics / Q000633:toxicity*; D004220:Disulfides / Q000737:chemistry; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009469:Neuromuscular Junction / Q000187:drug effects; D018733:Nicotinic Antagonists / Q000737:chemistry* / Q000633:toxicity*; D011487:Protein Conformation; D011978:Receptors, Nicotinic / Q000187:drug effects*; D012996:Solutions; D017841:Trimeresurus / Q000235:genetics / Q000378:metabolism
D003435:Crotalid Venoms; D004220:Disulfides; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; D012996:Solutions; C077895:waglerin