TY - JOUR
T1 - Intersubunit bridge formation governs agonist efficacy at nicotinic acetylcholine alpha4beta2 receptors
T2 - Unique role of halogen bonding revealed
AU - Rohde, Line Aagot Hede
AU - Ahring, Philip Kiær
AU - Jensen, Marianne Lerbech
AU - Nielsen, Elsebet Østergaard
AU - Peters, Dan
AU - Helgstrand, Charlotte
AU - Krintel, Christian
AU - Harpsøe, Kasper
AU - Gajhede, Michael
AU - Kastrup, Jette Sandholm
AU - Balle, Thomas
N1 - Keywords: acetylcholine binding protein; lymnaea stagnalis; crystal structure; nicotinic acetylcholine receptor; agonist ; efficacy
PY - 2012/2/3
Y1 - 2012/2/3
N2 - 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 intersub-unit 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.
AB - 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 intersub-unit 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.
KW - Former Faculty of Pharmaceutical Sciences
U2 - 10.1074/jbc.M111.292243
DO - 10.1074/jbc.M111.292243
M3 - Journal article
C2 - 22170047
SN - 0021-9258
VL - 287
SP - 4248
EP - 4259
JO - The Journal of Biological Chemistry
JF - The Journal of Biological Chemistry
IS - 6
ER -
