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

Rohde, Line Aagot Hede; Ahring, Philip Kiær; Jensen, Marianne Lerbech; Nielsen, Elsebet Østergaard; Peters, Dan; Helgstrand, Charlotte LU ; Krintel, Christian LU ; Harpsøe, Kasper; Gajhede, Michael and Kastrup, Jette Sandholm Jensen (2012) In Journal of Biological Chemistry 287(6). p.4248-4259
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... (More)
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. (Less)
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author
publishing date
type
Contribution to journal
publication status
published
in
Journal of Biological Chemistry
volume
287
issue
6
pages
4248 - 4259
publisher
ASBMB
external identifiers
  • scopus:84856756647
ISSN
1083-351X
DOI
10.1074/jbc.M111.292243
language
Unknown
LU publication?
no
id
729bcc4a-04d4-4c9e-ab11-cdf0e003f6b3
date added to LUP
2017-06-10 06:50:26
date last changed
2017-09-17 09:48:47
@article{729bcc4a-04d4-4c9e-ab11-cdf0e003f6b3,
  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.},
  author       = {Rohde, Line Aagot Hede and Ahring, Philip Kiær and Jensen, Marianne Lerbech and Nielsen, Elsebet Østergaard and Peters, Dan and Helgstrand, Charlotte and Krintel, Christian and Harpsøe, Kasper and Gajhede, Michael and Kastrup, Jette Sandholm Jensen},
  issn         = {1083-351X},
  language     = {und},
  number       = {6},
  pages        = {4248--4259},
  publisher    = {ASBMB},
  series       = {Journal of Biological Chemistry},
  title        = {Intersubunit bridge formation governs agonist efficacy at nicotinic acetylcholine α4β2 receptors : unique role of halogen bonding revealed},
  url          = {http://dx.doi.org/10.1074/jbc.M111.292243},
  volume       = {287},
  year         = {2012},
}