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A Role for Leu118 of Loop E in Agonist Binding to the 7 Nicotinic Acetylcholine Receptor

Structural Bioinformatics and Computational Biochemistry Unit, Department of Biochemistry (S.A., R.V., M.S.P.S., P.C.B.) and Department of Physiology, Anatomy, and Genetics (A.K.J., D.B.S.), University of Oxford, Oxford, United Kingdom; Department of Applied Biological Chemistry, School of Agriculture, Kinki University, Nara, Japan (M.S., H.N., K.M.); and Graduate School of Agriculture, Kyoto University, Kyoto, Japan (M.A.)

Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels mediating fast cholinergic synaptic transmission in the brain and at neuromuscular junctions. We used the structure of the acetylcholine binding protein from Lymnaea stagnalis to model the chicken 7 agonist-binding domain. The initial models and a preliminary docking study suggested that position Leu118 may play an important role in determining agonist actions on 7. A prediction from these in silico studies, that L118E and L118D would retain binding to acetylcholine but L118K and L118R would not, was confirmed in electrophysiological studies on functional recombinant mutant receptors expressed in Xenopus laevis oocytes. The functional studies also demonstrated that residues at position 118 have a dramatic effect on the actions of imidacloprid (a partial agonist of wild-type 7 receptors) and its des-nitro derivative. Molecular dynamics simulations confirmed that Leu118 can strongly influence agonist binding and that the model was robust in terms of its prediction for acetylcholine binding. Together, the results indicate a role for Leu118 in influencing agonist actions on 7 nAChRs.

Address correspondence to: David B. Sattelle, University of Oxford, South Parks Road, Oxford OX1 3QX, UK. E-mail: david.sattelle{at}anat.ox.ac.uk