The mechanism for acetylcholine receptor inhibition by alpha-neurotoxins and species-specific resistance to alpha-bungarotoxin revealed by NMR.
The structure of a peptide corresponding to residues 182-202 of the acetylcholine receptor alpha1 subunit in complex with alpha-bungarotoxin was solved using NMR spectroscopy. The peptide contains the complete sequence of the major determinant of AChR involved in alpha-bungarotoxin binding. One face of the long beta hairpin formed by the AChR peptide consists of exposed nonconserved residues, which interact extensively with the toxin. Mutations of these receptor residues confer resistance to the toxin. Conserved AChR residues form the opposite face of the beta hairpin, which creates the inner and partially hidden pocket for acetylcholine. An NMR-derived model for the receptor complex with two alpha-bungarotoxin molecules shows that this pocket is occupied by the conserved alpha-neurotoxin residue R36, which forms cation-pi interactions with both alphaW149 and gammaW55/deltaW57 of the receptor and mimics acetylcholine.
Samson
Abraham
A
Department of Structural Biology, The Weizmann Institute of Science, Rehovot, Israel.
Scherf
Tali
T
Eisenstein
Miriam
M
Chill
Jordan
J
Anglister
Jacob
J
D000595:Amino Acid Sequence / Q000502:physiology; D000818:Animals; D002038:Bungarotoxins / Q000378:metabolism*; D007473:Ion Channels / Q000737:chemistry / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D008954:Models, Biological; D008969:Molecular Sequence Data; D009420:Nervous System / Q000187:drug effects / Q000378:metabolism*; D009469:Neuromuscular Junction / Q000187:drug effects / Q000378:metabolism*; D009498:Neurotoxins / Q000378:metabolism*; D010446:Peptide Fragments / Q000737:chemistry* / Q000187:drug effects; D011485:Protein Binding / Q000502:physiology; D017433:Protein Structure, Secondary / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000502:physiology; D011978:Receptors, Nicotinic / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism; D013570:Synaptic Membranes / Q000187:drug effects / Q000378:metabolism; D064569:alpha7 Nicotinic Acetylcholine Receptor
D002038:Bungarotoxins; D007473:Ion Channels; D009498:Neurotoxins; D010446:Peptide Fragments; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor