Intersubunit bridge formation governs agonist efficacy at nicotinic acetylcholine alpha4beta2 receptors: Unique role of halogen bonding revealed

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 - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

IS - 6

ER -