Abstract
G protein-coupled receptors (GPCRs) recognize a wide variety of extracellular
ligands to control diverse physiological processes. Compounds that
bind to such receptors can either stimulate, fully or partially (full
or partial agonists), or reduce (inverse agonists) the receptors'
basal activity and receptor-mediated signaling. Various studies have
shown that the activation of receptors through binding of agonists
proceeds by conformational changes as the receptor switches from
a resting to an active state leading to G protein signaling. Yet
the molecular basis for differences between agonists and inverse
agonists is unclear. These different classes of compounds are assumed
to switch the receptors' conformation in distinct ways. It is not
known, however, whether such switching occurs along a linear 'on-off'
scale or whether agonists and inverse agonists induce different switch
mechanisms. Using a fluorescence-based approach to study the alpha2A-adrenergic
receptor (alpha(2A)AR), we show that inverse agonists are differentiated
from agonists in that they trigger a very distinct mode of a receptor's
switch. This switch couples inverse agonist binding to the suppression
of activity in the receptor.
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