A structural model of agonist binding to the alpha3beta4 neuronal nicotinic receptor.

(alpha3)2(beta4)3 is the most abundant type of neuronal nicotinic ACh receptor (nAChR) mediating cholinergic actions on the autonomic nervous system. Studies to refine or devise drugs selectively acting on (alpha3)2(beta4)3 receptors would benefit from a detailed description of the hitherto unclear agonist-binding domain. The present study reports a three-dimensional model for the ligand-binding domain (LBD) of this receptor either in its unoccupied or agonist-bound conformation. The receptor model was based on the structure of the acetylcholine-binding protein (AChBP), and was obtained using molecular modelling techniques. ACh, nicotine and cytisine (full agonists), muscarine (a selective agonist of muscarinic ACh receptors) and the allosteric modulator eserine were docked into the binding pockets of the receptor model. Simulated agonist-receptor complexes were compared with the agonist-binding complex of the AChBP, as well as of the (alpha4)2(beta2)3 type of nAChR, which is the commonest in the brain. Agonist docking identified discrete amino-acid residues of the beta subunits important for pharmacological selectivity of nAChRs. The predicted affinity of muscarine for the nAChR was low, suggesting the present model to be suitable for effective discrimination of nicotinic agonist binding versus nonselective cholinergic binding. Furthermore, the current model outlined a potential binding site for the allosteric modulator eserine, the site of action of which has remained elusive. The present LBD model of the receptor in its free state provides a novel structural framework to interpret experimental observations and a useful template for future investigations to develop (alpha3)2(beta4)3-selective ligands.