Structural determinants of selective alpha-conotoxin binding to a nicotinic acetylcholine receptor homolog AChBP

Proceedings of the National Academy of Sciences of the United States of America
Chris UlensT K Sixma

Abstract

The nicotinic acetylcholine receptor (nAChR) is the prototype member of the superfamily of pentameric ligand-gated ion channels. How the extracellular ligand-binding domain coordinates selective binding of ligand molecules to different subtypes of the receptor is unknown at the structural level. Here, we present the 2.2-A crystal structure of a homolog of the ligand-binding domain of the nAChR, Aplysia californica AChBP (Ac-AChBP), in complex with alpha-conotoxin ImI. This conotoxin is unique in its selectivity toward the neuronal alpha3beta2 and alpha7 nAChR, a feature that is reflected in its selective binding to Ac-AChBP compared with other AChBP homologs. We observe a network of interactions between the residues of the ligand-binding site and the toxin, in which ImI Arg-7 and Trp-10 play a key role. The toxin also forms interactions in the ligand-binding site that were not seen in the complex of Ac-AChBP with PnIA(A10L D14K), a conotoxin variant that lacks binding selectivity to AChBP homologs. In combination with electrophysiological recordings obtained by using the wild-type alpha7 nAChR and L247T mutant, we show that conotoxin ImI inhibits ion conduction by stabilizing the receptor in a desensitized conformation. Compari...Continue Reading

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Citations

Feb 12, 2013·Molecular Neurobiology·Jianliang ZhangXiaomin Wang
Jul 16, 2013·Biochemical Pharmacology·Mieke NysChris Ulens
Feb 24, 2011·Journal of Agricultural and Food Chemistry·Motohiro Tomizawa, John E Casida
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Jun 11, 2008·Proceedings of the National Academy of Sciences of the United States of America·Myunggi YiHuan-Xiang Zhou
Jan 31, 2008·Proceedings of the National Academy of Sciences of the United States of America·Motohiro TomizawaJohn E Casida
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Jul 10, 2014·Proceedings of the National Academy of Sciences of the United States of America·Katarzyna KaczanowskaPalmer Taylor
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Feb 12, 2008·Trends in Molecular Medicine·Jean-Pierre Changeux, Antoine Taly

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