Structural characterization of binding mode of smoking cessation drugs to nicotinic acetylcholine receptors through study of ligand complexes with acetylcholine-binding protein

Prakash Rucktooa; Claire A Haseler; René van Elk; August B Smit; Timothy Gallagher; Titia K Sixma

doi:10.1074/jbc.M112.360347

Structural characterization of binding mode of smoking cessation drugs to nicotinic acetylcholine receptors through study of ligand complexes with acetylcholine-binding protein

J Biol Chem. 2012 Jul 6;287(28):23283-93. doi: 10.1074/jbc.M112.360347. Epub 2012 May 2.

Authors

Prakash Rucktooa¹, Claire A Haseler, René van Elk, August B Smit, Timothy Gallagher, Titia K Sixma

Affiliation

¹ Division of Biochemistry and Center for Biomedical Genetics, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.

Abstract

Smoking cessation is an important aim in public health worldwide as tobacco smoking causes many preventable deaths. Addiction to tobacco smoking results from the binding of nicotine to nicotinic acetylcholine receptors (nAChRs) in the brain, in particular the α4β2 receptor. One way to aid smoking cessation is by the use of nicotine replacement therapies or partial nAChR agonists like cytisine or varenicline. Here we present the co-crystal structures of cytisine and varenicline in complex with Aplysia californica acetylcholine-binding protein and use these as models to investigate binding of these ligands binding to nAChRs. This analysis of the binding properties of these two partial agonists provides insight into differences with nicotine binding to nAChRs. A mutational analysis reveals that the residues conveying subtype selectivity in nAChRs reside on the binding site complementary face and include features extending beyond the first shell of contacting residues.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetylcholine / metabolism
Alkaloids / chemistry*
Alkaloids / metabolism
Animals
Aplysia / metabolism
Azocines / chemistry
Azocines / metabolism
Benzazepines / chemistry*
Benzazepines / metabolism
Binding Sites / genetics
Binding, Competitive
Carrier Proteins / chemistry*
Carrier Proteins / genetics
Carrier Proteins / metabolism
Cell Line
HEK293 Cells
Humans
Kinetics
Ligands
Models, Molecular
Mutation
Nicotine / chemistry
Nicotine / metabolism
Nicotinic Agonists / chemistry
Nicotinic Agonists / metabolism
Protein Binding
Protein Structure, Secondary
Protein Structure, Tertiary
Quinolizines / chemistry
Quinolizines / metabolism
Quinoxalines / chemistry*
Quinoxalines / metabolism
Receptors, Nicotinic / chemistry*
Receptors, Nicotinic / genetics
Receptors, Nicotinic / metabolism
Smoking Cessation
Varenicline
alpha7 Nicotinic Acetylcholine Receptor

Substances

Alkaloids
Azocines
Benzazepines
Carrier Proteins
Chrna7 protein, human
Ligands
Nicotinic Agonists
Quinolizines
Quinoxalines
Receptors, Nicotinic
alpha7 Nicotinic Acetylcholine Receptor
nicotinic receptor alpha4beta2
cytisine
Nicotine
Acetylcholine
Varenicline

Associated data

PDB/4AFO
PDB/4AFT