Structural determinants for alpha-neurotoxin sensitivity in muscle nAChR and their implications for the gating mechanism |
| |
Authors: | Dellisanti Cosma D Yao Yun Stroud James C Wang Zuo-Zhong Chen Lin |
| |
Institution: | 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. |
| |
Abstract: | 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. |
| |
Keywords: | |
本文献已被 PubMed 等数据库收录! |
|