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

J Biol Chem. 2012 Feb 3;287(6):4248-59. doi: 10.1074/jbc.M111.292243. Epub 2011 Dec 13.


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.

MeSH terms

  • Animals
  • Azepines / chemistry*
  • Azepines / metabolism
  • Cholinergic Agonists / chemistry*
  • Cholinergic Agonists / metabolism
  • Crystallography, X-Ray
  • HEK293 Cells
  • Halogens / chemistry*
  • Halogens / metabolism
  • Humans
  • Lymnaea
  • Protein Structure, Quaternary
  • Protein Structure, Secondary
  • Pyridines / chemistry*
  • Pyridines / metabolism
  • Receptors, Nicotinic / chemistry*
  • Receptors, Nicotinic / metabolism


  • 1-(5-ethoxypyridin-3-yl)-1,4-diazepane
  • Azepines
  • Cholinergic Agonists
  • Halogens
  • Pyridines
  • Receptors, Nicotinic
  • alpha(4)beta(4) nicotinic receptor

Associated data

  • PDB/3U8J
  • PDB/3U8K
  • PDB/3U8L
  • PDB/3U8M
  • PDB/3U8N