Intersubunit bridge formation governs agonist efficacy at nicotinic acetylcholine α4β2 receptors: unique role of halogen bonding revealed

Research output: Contribution to journalArticle

Abstract

The α4β2 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 α4β2 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 α4β2 and the acetylcholine-binding protein from Lymnaea stagnalis (Ls-AChBP) confirms Ls-AChBP as structural surrogate for α4β2 receptors. Crystal structures of five agonists with efficacies at α4β2 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.

Details

Authors
  • 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 Jensen Kastrup
External organisations
  • University of Copenhagen
Original languageUnknown
Pages (from-to)4248-4259
JournalJournal of Biological Chemistry
Volume287
Issue number6
Publication statusPublished - 2012
Publication categoryResearch
Peer-reviewedYes
Externally publishedYes