3U8K: Crystal structure of the acetylcholine binding protein (AChBP) from Lymnaea stagnalis in complex with NS3573 (1-(5-ethoxypyridin-3-yl)-1,4-diazepane)

Citation:
Abstract
The alpha4beta2 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 alpha4beta2 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 alpha4beta2 and the acetylcholine-binding protein from Lymnaea stagnalis (Ls-AChBP) confirms Ls-AChBP as structural surrogate for alpha4beta2 receptors. Crystal structures of five agonists with efficacies at alpha4beta2 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.
PDB ID: 3U8KDownload
MMDB ID: 95749
PDB Deposition Date: 2011/10/17
Updated in MMDB: 2011/12
Experimental Method:
x-ray diffraction
Resolution: 2.47  Å
Source Organism:
Similar Structures:
Biological Unit for 3U8K: pentameric; determined by author and by software (PISA)
Molecular Components in 3U8K
Label Count Molecule
Proteins (5 molecules)
5
Acetylcholine-binding Protein
Molecule annotation
Chemicals (8 molecules)
1
5
2
1
3
2
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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