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A ligand is a specific chemical signal molecule that fits into a three-dimensional site on its protein receptor (Figure 7.3A). Binding of the signaling ligand causes the receptor protein to change its three-dimensional shape, and that conformational change initiates a cellular response. The ligand does not contribute further to this response. In fact, the ligand is usually not changed; its role is purely to “knock on the door.”

The sensitivity of a cell to a signal is determined in part by the affinity of the cell’s receptors for the signal ligand—the likelihood that the receptor will bind to the ligand at any given ligand concentration. Receptors (R) bind to their ligands (L) according to chemistry’s law of mass action. This means that the binding is reversible:

R + L ⇌ RL                                             (7.1)

For most ligand–receptor complexes (RL), binding is favored. Reversibility is important, however, because if the ligand were never released, the receptor would be continuously stimulated and the cell would never stop responding.

As with any reversible chemical reaction, the binding and dissociation processes each have a rate constant, here designated k₁ and k₂:

A rate constant relates the rate of a reaction to the concentration(s) of the reactant(s):

Rate of binding = k₁[R][L]                         (7.4)

Rate of dissociation = k₂[RL]                    (7.5)

where “[ ]” indicates the concentration of the substance inside the brackets. Binding of a receptor to a ligand is reversible, and when equilibrium is reached the rate of binding equals the rate of dissociation:

k₁[R][L] = k₂[RL]                                   (7.6)

If this is rearranged, we get:

K_D, the dissociation constant, is a measure of the affinity of the receptor for its ligand. The lower the K_D, the higher the affinity of the ligand for its receptor. Some receptors have very low K_D values, which allows them to bind their ligands at very low ligand concentrations; other receptors have higher K_D values and need more ligand to be present to set off their signal transduction pathways.

An entire field of biology and medicine—called pharmacology—is devoted to the study of drugs. These molecules are usually thought of as synthetic, but some are natural substances, such as caffeine (see Figure 7.3B). Drugs function as ligands that bind specific receptors. In the discovery and design of new drugs, it is helpful to know the specific receptor that the drug will bind, because then it is possible to determine the K_D value of its binding. This is one factor that can be taken into consideration when determining dosage levels. Of course, many drugs have side effects, and these are also dosage-dependent.

Question

As with the binding of enzyme to substrate, the binding of caffeine and adenosine is noncovalent. Both substances bind to a specific site on the receptor by their shape and by interactions, including hydrophobic interactions (the rings).

What happens when a ligand binds to a receptor? When we discussed small molecules binding to proteins in Key Concept 3.2, we described how proteins often change shape when bound. This is exactly what happens to receptors. The change in the receptor’s shape may expose a previously hidden group of amino acids on the protein that participate in a biochemical activity. This activity may be the binding of another molecule, such as another protein (e.g., a G protein, discussed below), or a substrate for an enzyme.

Instead of the ligand, other chemicals that resemble it can bind to the receptor. Agonists are chemicals that set a receptor into signal transduction mode just as the ligand does. In contrast, inhibitors, or antagonists, bind to the receptor and “freeze” it in place, preventing the real ligand from binding, but do not set off signal transduction. Agonists and antagonists can be natural, or we can make them in the lab once we know the details of receptor–ligand binding.

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Many substances that alter human behavior bind to specific receptors in the brain and prevent the binding of the receptors’ specific ligands. One example is caffeine, which is probably the world’s most widely consumed stimulant. In the brain, the nucleoside adenosine acts as a ligand that binds to a receptor on nerve cells, initiating a signal transduction pathway that reduces brain activity, especially feelings of active wakefulness. Because caffeine has a molecular structure similar to that of adenosine, it also binds to the adenosine receptor (Figure 7.3B). But in this case binding does not initiate a signal transduction pathway. Rather, it “ties up” the receptor, preventing adenosine binding and thereby allowing continued nerve cell activity and an active feeling.