Intersubunit bridge formation governs agonist efficacy at nicotinic acetylcholine alpha4beta2 receptors: Unique role of halogen bonding revealed

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The a4ß2 subtype of the nicotinic acetylcholine receptor (nAChR) has been pursued as a drug target for treatment of psychiatric and neurodegenerative disorders and smoking cessation aids for decades. Still, a thorough understanding of structure-function relationships of a4ß2 agonists is lacking. Using binding experiments, electrophysiology and X-ray crystallography we have investigated a consecutive series of five prototypical pyridine-containing agonists derived from 1-(pyridin-3-yl)-1,4-diazepane. A correlation between binding affinities at a4ß2 and the acetylcholine binding protein from Lymnaea stagnalis (Ls-AChBP) confirms Ls-AChBP as structural surrogate for a4ß2 receptors. Crystal structures of five agonists with efficacies at a4ß2 from 21-76% were determined in complex with Ls-AChBP. No variation in closure of loop C is observed despite large efficacy variations. Instead, the efficacy of a compound appears tightly coupled to its ability to form a strong inter-subunit bridge linking the primary and complementary binding interfaces. For the tested agonists, a specific halogen bond was observed to play a large role in establishing such strong inter-subunit anchoring.
Original languageEnglish
JournalThe Journal of Biological Chemistry
Issue number6
Pages (from-to)4248-4259
Publication statusPublished - 3 Feb 2012

Bibliographical note

Keywords: acetylcholine binding protein; lymnaea stagnalis; crystal structure; nicotinic acetylcholine receptor; agonist ; efficacy

ID: 35936290