Principles of cell signaling - UT Southwestern

39057_ch14_cellbio.qxd 8/28/06 5:11 PM Page 594
How do ligands activate (or not activate) a
receptor? Most of the basic regulatory activities
of receptors can be described by a simple scheme
that considers the receptors as having two interconvertible
conformations, inactive (R) and
active (R*). R and R* are in equilibrium, which
is described by the equilibrium constant J.
Because unliganded receptors are usually
minimally active, J1), then ligand binding
will shift the conformation to the R* state to an
equivalent extent (i.e., J*/J>>1). The relative
activation by a saturating concentration of ligand,
J*/J, will exactly equal the ligand’s relative
selectivity for the active receptor conformation,
K*/K. This argument is generally valid for the regulation
of a protein’s activity by any regulatory
ligand.
This model explains many properties of receptors
and their ligands both simply and quantitatively.
• First, J must be greater than zero for the
equilibrium to exist. Thus, even unliganded
receptor has some activity.
Overexpressed receptors frequently display
their intrinsic low activity.
• Because physiological receptors are
nearly inactive in the absence of ligand,
J must be much less than 1 and is probably
less than 0.01; most receptors are
less than 1% active without agonist.
• Ligands can vary in their selectivities
between R and R*. Their abilities to activate
will also vary. Some ligands, referred
to as agonists, can drive formation
of appreciable R*. Others, known as partial
agonists, will promote submaximal
activation. Chemical manipulation
of a ligand’s structure will often alter its
activity as an agonist. These relationships
are depicted graphically in FIGURE
14.3.
• A ligand that binds equally well to both
the R and R* states will not cause activation.
However, such a ligand may still
occupy the binding site and thereby
competitively inhibit binding of an activating
ligand. Such competitive inhibitors,
referred to as antagonists, are
frequently used as drugs to block unwanted
activation of a receptor in various
disease states.
• A ligand that binds preferentially to R
594 CHAPTER 14 Principles of cell signaling