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J. Biol. Chem., Vol. 269, Issue 12, 8808-8816, Mar, 1994
SM Sine, P Quiram, F Papanikolaou, HJ Kreienkamp and P Taylor
Studies with site-directed labeling reagents have identified residues near
the ligand binding pocket of the nicotinic acetylcholine receptor. Among
these residues are three conserved tyrosines, Tyr-93, Tyr-190, and Tyr-198
of the alpha subunit. Previous studies combined mutagenesis, expression in
Xenopus oocytes, and dose-response analysis to examine contributions of
these tyrosines to agonist affinity. In this study, we prepared a series of
mutants at each position, expressed them in 293 HEK cells, and studied
binding of agonists and antagonists to mutant receptors on intact cells. We
show that all three tyrosines contribute to binding of agonists, and that
each tyrosine contributes roughly equally to the binding energy. Although
the contributions are roughly equivalent, the nature of the contribution is
not equivalent at each position. For Tyr-93 and Tyr-190 the aromatic
hydroxyl is essential, whereas for Tyr-198 aromaticity of the side chain is
essential. Nearly identical results were obtained for the elementary
quaternary ligand tetramethylammonium, indicating that these tyrosines
contribute to stabilization of the quaternary ammonium portion of agonist.
Tyr-190 and Tyr-198 also contribute to binding of the competitive
antagonist dimethyl-d-tubocurarine; the side chain specificity for binding
supports tyrosine interactions with one of two quaternary ammonium groups
in dimethyl-d-tubocurarine. Y190F, in addition to altering binding
affinity, also affects the equilibrium between activatable and desensitized
receptor states.
Conserved tyrosines in the alpha subunit of the nicotinic acetylcholine receptor stabilize quaternary ammonium groups of agonists and curariform antagonists
Department of Physiology and Biophysics, Mayo Foundation, Rochester, Minnesota 55905.
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