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Vol. 56, Issue 5, 1031-1041, November 1999
Division of Physical Biochemistry, Medical Research Council
National Institute for Medical Research, London, United Kingdom
Transmembrane domain 6 of the muscarinic acetylcholine (ACh) receptors
is important in ligand binding and in the conformational transitions of
the receptor but the roles of individual residues are poorly
understood. We have carried out a systematic alanine-scanning mutagenesis study on residues Tyr381 to Val387 within the binding domain of the M1 muscarinic ACh receptor. The seven
mutations were then analyzed to define the effects on receptor
expression, agonist and antagonist binding, and signaling efficacy.
Tyr381Ala produced a 40-fold reduction in ACh affinity and a 50-fold
reduction in ACh-signaling efficacy. Leu386Ala had similar but smaller
effects. Asn382Ala caused the largest inhibition of antagonist binding. The roles of the hydroxyl group and benzene ring of Tyr381 were probed
further by comparative analysis of the Tyr381Phe and Tyr381Ala mutants
using three series of ligands: ACh analogs, azanorbornane- and
quinuclidine-based ligands, and atropine analogs. These data suggested
that the hydroxyl group of Tyr381 is primarily involved in forming
hydrogen bond interactions with the oxygen atoms present in the side
chain of ACh. We propose that this interaction is established in the
ground state and preserved in the activated state of the
receptor. In contrast, the Tyr381 benzene ring may form a
cation-
interaction with the positively charged head group of ACh
that contributes to the activated state of the receptor but not the
ground state. However, the hydroxyl group and benzene ring of Tyr381
both participate in interactions with azanorbornane- and
quinuclidine-based ligands and atropine analogs in the ground state as
well as the activated state of the receptor.
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