Structural Determinants for α-Neurotoxin Sensitivity in Muscle nAChR and Their Implications for the Gating Mechanism

Cosma Dellisanti, Yun Yao, James C. Stroud, Zuo-Zhong Wang and Lin Chen

volume 1 | issue 4

July/August
Pages: 234 - 237

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Neurotoxins from snake venoms act as potent antagonists on the nicotinic acetylcholine receptors (nAChRs). α-Neurotoxins such as α-bungarotoxin (α-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 α-neurotoxins via specific amino acid substitutions in their muscle-type nAChR α1 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 α1 bound to α-Btx. Our structure suggests that α-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 α-Btx binding interface on nAChR α1 but away from the agonist binding site. These mutations can interfere with the binding of α-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.

Authors

Cosma Dellisanti

University of Southern California

Yun Yao

Zilkha Neurogenetic Institute, University of Southern California

James C. Stroud

University of California Los Angeles

Zuo-Zhong Wang