title: Intersubunit bridge formation governs agonist efficacy at nicotinic acetylcholine α4β2 receptors: unique role of halogen bonding revealed.
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.
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Copenhagen 2100, Denmark.
authors.forename: Line Aagot Hede
authors.initials: LA
authors.lastname: Rohde
authors.forename: Philip Kiær
authors.initials: PK
authors.lastname: Ahring
authors.forename: Marianne Lerbech
authors.initials: ML
authors.lastname: Jensen
authors.forename: Elsebet Østergaard
authors.initials: EØ
authors.lastname: Nielsen
authors.forename: Dan
authors.initials: D
authors.lastname: Peters
authors.forename: Charlotte
authors.initials: C
authors.lastname: Helgstrand
authors.forename: Christian
authors.initials: C
authors.lastname: Krintel
authors.forename: Kasper
authors.initials: K
authors.lastname: Harpsøe
authors.forename: Michael
authors.initials: M
authors.lastname: Gajhede
authors.forename: Jette Sandholm
authors.initials: JS
authors.lastname: Kastrup
authors.forename: Thomas
authors.initials: T
authors.lastname: Balle
mesh_terms: D000818:Animals; D001381:Azepines / Q000737:chemistry* / Q000378:metabolism; D018679:Cholinergic Agonists / Q000737:chemistry* / Q000378:metabolism; D018360:Crystallography, X-Ray; D057809:HEK293 Cells; D006219:Halogens / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008195:Lymnaea; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D011725:Pyridines / Q000737:chemistry* / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000737:chemistry* / Q000378:metabolism
chemical_list: C561587:1-(5-ethoxypyridin-3-yl)-1,4-diazepane; D001381:Azepines; D018679:Cholinergic Agonists; D006219:Halogens; D011725:Pyridines; D011978:Receptors, Nicotinic; C427403:alpha(4)beta(4) nicotinic receptor