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Publication Abstract from PubMed

The alpha4beta2 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 alpha4beta2 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 alpha4beta2 and the acetylcholine-binding protein from Lymnaea stagnalis (Ls-AChBP) confirms Ls-AChBP as structural surrogate for alpha4beta2 receptors. Crystal structures of five agonists with efficacies at alpha4beta2 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.

Intersubunit bridge formation governs agonist efficacy at nicotinic acetylcholine alpha4beta2 receptors: unique role of halogen bonding revealed.,Rohde LA, Ahring PK, Jensen ML, Nielsen EO, Peters D, Helgstrand C, Krintel C, Harpsoe K, Gajhede M, Kastrup JS, Balle T J Biol Chem. 2012 Feb 3;287(6):4248-59. Epub 2011 Dec 13. PMID:22170047^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.