How receptors recognize signals

A cell is bathed in thousands of kinds of molecules, yet most of its receptors respond to just one kind of signal. That selectivity comes from shape, and how tightly a receptor holds its signal can be measured.

Ligands and specificity

A receptor recognizes its signaling molecule by shape, much as an enzyme recognizes the molecule it acts on. (An enzyme holds its starting material, the substrate, in a pocket called the active site, and only molecules of the right shape fit.) The signaling molecule that binds to a receptor is called a ligand. Ligands range from steroids to proteins.

Most receptors bind only a ligand with a very particular structure and ignore everything else. This selectivity is specificity.

The ligand is held by weak attractions, not by the strong bonds in which atoms share electrons, so the binding is noncovalent. Binding happens by chance: the two molecules have to bump into each other lined up the right way and with enough energy. The pair they form is a ligand–receptor complex. It lasts for a while and then falls apart, so binding is reversible.

The ligand changes the receptor

Here receptors and enzymes part ways. An enzyme converts its substrate into a product. A receptor usually leaves its ligand unchanged; instead, the ligand changes the receptor. Binding causes a conformational change (a change in the receptor’s three-dimensional shape) that switches on the receptor’s ability to start a cellular response.

When the ligand lets go, the receptor returns to its inactive shape. So a receptor stays active only as long as its ligand is bound.

Measuring affinity with Kd

How tightly a receptor holds its ligand is its affinity. Some receptors grip their ligand firmly; others let go easily.

At any moment, some ligands are binding receptors while some complexes are falling apart. Soon the two happen at the same rate and the amounts stop changing, a balance called equilibrium. At equilibrium, affinity is measured by the dissociation constant, written Kd:

Kd = [ligand] × [receptor] ÷ [ligand–receptor complex]

Square brackets mean concentration, the amount of a substance in a given volume, and [receptor] counts only receptors with no ligand bound. Kd also equals the ratio of how readily complexes fall apart to how readily they form. A receptor that holds on tightly forms complexes that rarely fall apart, so its Kd is small.

What Kd tells you

The most useful fact about Kd comes from the moment when half the receptors have ligand bound. Then empty receptors and complexes are present in equal amounts, so they cancel out of the equation, leaving Kd = [ligand]. In other words, Kd is the ligand concentration at which half of the receptors are occupied. That lets you predict a response:

• If the ligand concentration is well above Kd, most receptors are occupied, and the cell is likely to respond.
• If the ligand concentration is far below Kd, few receptors are occupied, and a response is unlikely.

Knowing a receptor’s Kd lets researchers predict whether a given amount of its signal will trigger a response.

Receptors on the surface and inside

A receptor has to sit where its ligand can reach it. Most signaling molecules can’t get through the oily interior of the plasma membrane, either because they’re hydrophilic (water-loving) or because they’re too large. Their receptors are cell surface receptors, proteins in the plasma membrane with a binding site facing outward. A typical cell carries dozens to hundreds of different kinds.

Hydrophobic (water-avoiding) signals, such as the steroid hormones estrogen and testosterone, can pass through the membrane. Their receptors, called intracellular receptors, are located inside the cell, in the cytosol or the nucleus.

Check yourselfHow is a ligand binding to its receptor like a substrate binding to an enzyme, and how is it different?

Both bind noncovalently and with high specificity. The difference is what happens next: an enzyme converts its substrate into a product, while a receptor leaves its ligand unchanged and undergoes a conformational change that activates it.