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

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Line Aagot Hede Rohde, Philip Kiær Ahring, Marianne Lerbech Jensen, Elsebet Østergaard Nielsen, Dan Peters, Charlotte Helgstrand, Christian Krintel, Kasper Harpsøe, Michael Gajhede, Jette Sandholm Kastrup, Thomas Balle

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