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Vol. 55, Issue 2, 195-201, February 1999
Molecular Pharmacology Group, Division of Biochemistry and
Molecular Biology, Institute of Biomedical and Life Sciences,
University of Glasgow, Glasgow, Scotland, United Kingdom
Compared with epinephrine, the relative intrinsic activity of a
series of partial agonists to activate fusion proteins between the
porcine alpha-2A adrenoceptor and the This is the first demonstration that the relative intrinsic activity
of a series of agonists can be modified by a point mutation in a G
protein rather than a receptor and indicates that the nature of a key
contact site between a G protein and a receptor can selectively regulate partial agonist function. We provide a model for this based on
the hydrophobicity of a key receptor-G protein 
-subunit of
Gi1 was reduced after a single-point mutation
(Cys351Gly) in the G protein. Although UK14304 was close to
a full agonist at the fusion construct containing wild-type
(Cys351)Gi1
, it was a partial agonist at
that containing Gly351Gi1. Moreover,
although clonidine functioned as a good partial agonist to activate the
fusion protein containing Cys351Gi1, it was
essentially an antagonist at the
Gly351Gi1-containing fusion protein. By
contrast, incorporation of Ile351Gi1 into
the fusion protein resulted in all partial agonists displaying higher
intrinsic activity relative to epinephrine to activate this fusion
protein than the one containing the wild-type G protein sequence.
-subunit interaction interface.
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