Intersubunit bridge formation governs agonist efficacy at nicotinic acetylcholine ?4?2 receptors: unique role of halogen bonding revealed.

ABSTRACT: The ?4?2 subtype of the nicotinic acetylcholine receptor 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 ?4?2 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 ?4?2 and the acetylcholine-binding protein from Lymnaea stagnalis (Ls-AChBP) confirms Ls-AChBP as structural surrogate for ?4?2 receptors. Crystal structures of five agonists with efficacies at ?4?2 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 intersubunit 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 intersubunit anchoring.

SUBMITTER: Rohde LA 

PROVIDER: S-EPMC3281707 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature