Structural determinants for alpha-neurotoxin sensitivity in muscle nAChR and their implications for the gating mechanism.
Neurotoxins from snake venoms act as potent antagonists on the nicotinic acetylcholine receptors (nAChRs). Alpha-neurotoxins such as alpha-bungarotoxin (alpha-Btx) selectively bind to the skeletal muscle nAChRs among other subtypes, causing failure of the neuromuscular transmission. Through evolution, some species including snakes and mongoose have developed resistance to alpha-neurotoxins via specific amino acid substitutions in their muscle-type nAChR alpha1 subunit, which constitutes most of the toxin-binding site. Here we analyze these sequence variations in the context of our recent crystal structure of the extracellular domain of the mouse nAChR alpha1 bound to alpha-Btx. Our structure suggests that alpha-Btx has evolved as an extremely potent antagonist of muscle nAChR by binding the receptor tightly, blocking its ligand site, and locking its conformation in a closed state. Conversely, most toxin-resistant mutations occur at the alpha-Btx binding interface on nAChR alpha1 but away from the agonist binding site. These mutations can interfere with the binding of alpha-Btx without having deleterious effect on the gating function. These analyses not only help understand the structural determinants for neurotoxin sensitivity in muscle-type nAChR, but also shed light on its gating mechanism.
Dellisanti
Cosma D
CD
Molecular and Computational Biology, Department of Chemistry and Norris Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90089-2910, USA.
Yao
Yun
Y
Stroud
James C
JC
Wang
Zuo-Zhong
ZZ
Chen
Lin
L
D000595:Amino Acid Sequence; D000818:Animals; D002038:Bungarotoxins / Q000378:metabolism / Q000494:pharmacology*; D004351:Drug Resistance; D019143:Evolution, Molecular; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects*; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism; D009154:Mutation; D009469:Neuromuscular Junction / Q000187:drug effects / Q000378:metabolism; D009498:Neurotoxins / Q000378:metabolism / Q000494:pharmacology*; D018733:Nicotinic Antagonists / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding; D011487:Protein Conformation; D021122:Protein Subunits; D011978:Receptors, Nicotinic / Q000737:chemistry / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D009435:Synaptic Transmission / Q000187:drug effects
D002038:Bungarotoxins; D008024:Ligands; D009498:Neurotoxins; D018733:Nicotinic Antagonists; D021122:Protein Subunits; D011978:Receptors, Nicotinic