Ligand Definition

In biochemistry, a ligand is any molecule or atom which binds reversibly to a protein. A ligand can be an individual atom or ion. It can also be a larger and more complex molecule made from many atoms. A ligand can be natural, as an organic or inorganic molecule. A ligand can also be made synthetically, in the laboratory. This is because the key properties of a ligand are found in its chemical structure. If that structure can be recreated in the laboratory, the synthetic ligand will be able to interact in the same ways a natural ligand acts.

How a Ligand Works

The ligand travels through the watery fluids of an organism, within the blood, tissues, or within a cell itself. The ligand travels at random, but once the concentration is high enough, a ligand will eventually reach a protein. Proteins receiving ligands can be receptors, channels, and can even be the start of a complex series of intertwined proteins. When the ligand binds to the protein, it undergoes a conformational change. This means that while no chemical bonds have been formed or broken, the physical action of the ligand fitting into the protein changes the overall shape of the entire structure. This can trigger many actions. In most cases, the movement of the protein itself activates another chemical pathway, or triggers the release of another messenger ligand, to carry the message to other receptors.

The reversibility of the bond between ligand and protein is a crucial aspect of all forms of life. If ligands bound irreversibly, they could not serve as messengers, and most biological processes would fall apart. If ligands were changed, the way an enzyme changes a substrate, the ligand would become something else after the interaction, and could not be as easily recycled as a messenger. Biologically active proteins are active because of their shape. This shape interacts with the chemistry of the ligand to create a stable connection between the two molecules, which will eventually reverse, leaving both molecules the same. In a substrate and enzyme reaction, the substrate is permanently changed.

It is this ability of the ligand, to activate a protein for a short amount of time and then be recycled, which allows for the biological control of many interactions. The amount of time a ligand spends attached to its receptor or specific protein is a function of the affinity between the ligand and the protein. If there is a high affinity, the ligand will tend to stick to the protein and modify its function for longer. If the ligand has a low affinity for the protein, it will be less likely to bond in the first place and will release from the receptor faster.

The affinity of a particular ligand for a particular protein is determined entirely by its chemical makeup and that of the binding site of the protein. At the binding site, amino acids will be exposed which tend to complement the desired ligand. The amino acids will match the ligand in certain aspects. For instance, both will be hydrophilic or hydrophobic. This increases the attraction between the substances. The amino acids tend to differ from the ligand in terms of electrical activity. If the ligand is positively charged, the binding site should be negatively charged. This creates the strongest interaction. In this way, proteins can obtain a certain degree of specificity for a ligand.

While this is the basis for how cells can begin to tell different molecules apart, it is also at the heart of one of an organism’s biggest problems. Many poisons and toxic substances are so toxic because of their ability to interfere with the protein-ligand binding process. Either the toxin directly binds to the protein itself, because it has a higher affinity, or the toxin otherwise prevents the normal bonding of a ligand to its target protein. Examples of ligands and some competitive toxins can be seen below.

Examples of a Ligand

Oxygen

One ligand that people often overlook is oxygen. In the bloodstream and body tissues, oxygen must reach all the mitochondria in the body if the organism is to survive. But, it is not an easy task to get oxygen everywhere. If oxygen were left to diffuse through the tissue to the cells, it can only pass a few cell layers thick. That is why all organisms of a certain size must contain some sort of circulatory system. Even still, it is hard to move the oxygen ligand where it is needed. Many organisms use specialized proteins for this.

In humans and other mammals, hemoglobin is the major blood protein responsible for transporting oxygen. The hemoglobin protein first attaches to a ligand called heme, which has an iron atom and can help bind oxygen. Thus, hemoglobin picks up oxygen in the lungs. As it travels to the body, the carbon dioxide content in the blood rises. As this happens, the pH lowers, and the conformation of hemoglobin changes. This forces the release of the ligand, oxygen, which can then be absorbed by the cells which need it.

A main competitor of oxygen is carbon monoxide. This is because carbon monoxide has a higher affinity for hemoglobin than oxygen has. In other words, once carbon monoxide is bound to the hemoglobin, it won’t come off. This means that someone exposed to large amounts of carbon monoxide will soon have all their hemoglobin saturated by the wrong ligand. Their body will have no ability to transfer oxygen to the brains and tissues. Even if the person gets oxygen after this, they can still suffocate because of their inability to transport the oxygen.

Dopamine

Dopamine is a ligand used heavily in the brain. When the brain releases dopamine, it is as a signal of a pleasure coming from success. In other words, dopamine is tied to the sensation of motivation. The dopamine receptors in your brain are activated when the ligand dopamine is released by the brain. When the receptors are full of dopamine, your brain feels as if you’ve done something good. This common reward center can be easily thrown off by drugs such as cocaine and methamphetamine.

These drugs, instead of being in direct competition with the ligand, actually increase its effectiveness. They do this by limiting the amount of dopamine which can be recycled. Thus, the brain stays in a constant state of feeling “rewarded”. This is the dangerous feeling which can easily lead to drug addiction. Even though logic tells you drugs are bad, the feelings produced by your brain and the extra dopamine feel real, and tell you to use the drug more.

Other Ligand Uses

Ligands are used in many other applications by cells. The proteins they control can range widely in type and function. Some ligands, like insulin, are used to signal various things to the metabolism of each cell. Another ligand, such as acetylcholine, is used by the brain to transfer nerve impulses between nerves. In this case, it opens an ligand-gated channel, which allows the electrical impulse to flow into the cell and down the length of it. This cell will then transmit acetylcholine to the next cell, and the signal will continue.

Some enzymes are controlled by regulatory ligands, which effectively turn the enzyme on. Without it, they do not have the proper shape to transform the molecules they operate on. When the ligand is present, however, these enzymes spring to life and function properly. Many ligands are needed for controlling the metabolism and other complex processes. Each ligand has a certain affinity, which is important, and also a point at which the receptors become saturated. Above this limit, no higher concentration of ligand will bring a greater reaction.

In general chemistry, a ligand may refer to any molecule bound to a transition metal. This is not the case in biology. In biology, a ligand is any molecule which attaches reversibly to a protein. These are typically used in cellular signaling and cellular regulation, but have many other uses.

Quiz

1. Which of the following is NOT a ligand?
A. Air
B. Insulin
C. Bacterial protein

Answer to Question #1
A is correct. Air is made of many different molecules. There is oxygen, nitrogen, helium, carbon dioxide, and a slew of other materials. Each one of these may be a ligand in some system, but they all cannot be one ligand. Insulin is a typical human ligand. While you might not think of it, a bacterial protein is a ligand for the antibody proteins produced in the immune system.

2. Select the true statement.
A. All ligands evolved for their specific protein
B. A ligand can only be used once
C. A ligand changes the conformation of the protein it affects

Answer to Question #2
C is correct. Anytime a substance bonds to a protein, even in a reversible way, it changes the shape of that protein. A ligand, once released from the receptor, can be used again if collected and recycled. Answer A is actually backwards. Typically, it is viewed that all proteins must have evolved for a specific ligand, as a ligand can be as simple as oxygen. Although, in complex systems in complex organisms, this begins to look like the chicken and the egg argument.

3. Which organism below DOES NOT use ligands?
A. Tree
B. Fish
C. Worm
D. All organisms use ligands

Answer to Question #3
D is correct. Ligand is just a fancy word for something that a protein attaches to. All life is based on DNA, which produces proteins. Since all life uses proteins, all life relies on some form of ligand or another.

References

  • Bruice, P. Y. (2011). Organic Chemistry (6th ed.). Boston: Prentice Hall.
  • Nelson, D. L., & Cox, M. M. (2008). Principles of Biochemistry. New York: W.H. Freeman and Company.
  • Widmaier, E. P., Raff, H., & Strang, K. T. (2008). Vander’s Human Physiology: The Mechanisms of Body Function (11th ed.). Boston: McGraw-Hill Higher Education.