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Vol. 53, Issue 4, 787-794, April 1998
-Conotoxin M1 Binding
Department of Pharmacology, University of California, San Diego, La
Jolla, California 92093 (N.S., P.M., C.K., H.O., B.M., P.T.) and
Department of Physiology and Biophysics, Mayo Clinic and
Foundation, Rochester, Minnesota 55455 (S.M.S.)
The two binding sites in the pentameric nicotinic acetylcholine
receptor of subunit composition 
2
are formed by
nonequivalent - and - subunit interfaces, which produce
site selectivity in the binding of agonists and antagonists. We show by
sedimentation analysis that 125I--conotoxin M1 binds
with high affinity to the - subunit dimers, but not to -
dimers, nor to , , and monomers, a finding consistent with
-conotoxin M1 selectivity for the interface in the intact
receptor measured by competition against -bungarotoxin binding. We
also extend previous identification of -conotoxin M1 determinants in
the and subunits to the subunit interface by mutagenesis of
conserved residues in the subunit. Most mutations of the subunit affect affinity similarly at the two sites, but Tyr93Phe,
Val188Lys, Tyr190Thr, Tyr198Thr, and Asp152Asn affect affinity in a
site-selective manner. Mutant cycle analysis reveals only weak or no
interactions between mutant and non- subunits, indicating that
side chains of the subunit do not interact with those of the or
subunits in stabilizing -conotoxin M1. The overall findings
suggest different binding configurations of -conotoxin M1 at the
- and - binding interfaces.
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