Ligands: An Overview

Within biochemistry, a ligand is defined as any molecule or atom that irreversibly binds to a receiving protein molecule, otherwise known as a receptor. When a ligand binds to its respective receptor, the shape and/or activity of the ligand is altered to initiate several different types of cellular responses. Such cellular responses are vital for the proliferation, migration, survival, and differentiation of cells within all multicellular organisms.

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Ligands and receptors

Any type of biological receptor will have a certain degree of specificity towards one or, at most, a few ligands to bind to their ligand-binding region. Ligand-activated receptors can be found on both the surface of the cell, as well as at various intracellular locations.

Cell-surface receptors

Some of the most widely studied cell-surface receptors include those belonging to the receptor tyrosine kinase (RTK) family, which is made up of a total of 58 different types of receptors. Each RTK has an extracellular domain that contains the ligand-binding site, a single hydrophobic transmembrane a helix and a cytosolic domain that houses a region that is responsible for protein-tyrosine kinase activity.

In addition to playing a crucial role in normal cellular processes ranging from growth and motility to differentiation and metabolism, the dysregulation of RTKs has been associated with a wide range of human diseases, most notably of which includes cancer.

Most of the ligands that bind to RTKs are soluble or membrane-bound peptide or protein hormones that can be monomeric, dimeric, or trimeric. Notably, the specificity between ligands and RTKs is not extremely strict, with ligands being capable of binding to more than one receptor and vice versa.

Some examples of ligands that bind to RTKs include nerve growth factor (NGF), platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), epidermal growth factor (EGF), and insulin. The binding of a ligand to most RTKs will result in the ligand-induced dimerization of these receptors, which will subsequently lead to a process known as autophosphorylation.

This process of autophosphorylation will either change the conformation of the kinase domain, which will increase their kinase activity or produce phosphorylated sequences that can be used by downstream intracellular signaling molecules that contain either Src homology 2 (SH2) or phosphotyrosine-binding (PTB) domains.

Intracellular receptors

Although most ligand receptors are present on the surface of the cell, several different types of intracellular receptors are involved in different signaling pathways within the cell. Nuclear receptors, which are also known as nuclear hormone receptors, are activated by lipid-soluble molecules such as steroid hormones, thyroid hormones, retinoids, and vitamin D.

Each of these ligands that bind to nuclear receptors can readily cross the plasma membrane, which is a unique characteristic that most of the other intracellular messengers are not capable of.

When a ligand binds to a nuclear receptor, the receptor undergoes a conformational change that prevents the ligand from dissociating from the receptor. The newly formed receptor-ligand complex can then bind to specific DNA sequences known as hormone response elements (HREs). There are four different types of HRE receptors, all of which originate from pairs of sequences with the consensus RGGTCA, with the R molecule representing purine.

Type I HRE receptors, for example, include androgen, estrogen, and progesterone receptors, all of which are anchored in the cytoplasm by chaperone proteins like HSP90. Once a ligand binds to any of these Type I receptors, the receptor is removed from the chaperone protein to allow for the ligand to enter into the nucleus to activate a wide range of target genes.

Type II receptors, of which include the thyroid hormones and retinoic acid receptors, which are instead present within the nucleus, can bind to their specific DNA response element with or without the assistance from a ligand.

Ligands for therapeutics

The estrogen receptor (ER) is a ligand-inducible transcription factor that is comprised of a central DNA binding domain, a disordered N-terminal activation function 1 (AF1) domain, and a C-terminal ligand-binding domain (LBD). Upon the binding of estrogen to its ER, transcription is activated through the recruitment of various cofactors and chromatin-modifying enzymes to specified chromatin sites.

Despite their regulatory role for protein production, the presence of ER in breast cancer, otherwise known as ER⁺ breast cancer, continues to claim the lives of approximately 50% of all women with cancer. Although certain ER-targeted agents have been shown to suppress ER transcriptional activity to a certain degree, they remain limited in their ability to fully degrade ER⁺ cancer cells.

As a result, several therapeutic ligands have been investigated for their ability to antagonize ER function by promoting the binding of ER to canonical DNA binding sites. Several novel ER variants have demonstrated their ability to suppress ER transcription and subsequent turnover of ER⁺ breast cancer cells.  

Aside from ligands that are being investigated for novel therapeutic purposes, chelating agents have traditionally utilized ligands to prevent or reduce metallic ion toxicity. For example, 2,3-Dimercaptopropanol, which is otherwise known as British anti-Lewisite (BAL), has been used for several decades for mercury poisoning treatment.

Another therapeutic chelating ligand includes that which is used for the treatment of hemochromatosis, which is a genetic condition that causes affected individuals to experience an accumulation of iron.

In addition to their usefulness in limiting the adverse effects of metallic ion accumulation, ligands have also been used for their inhibitory effects against selected metalloenzymes or to facilitate the redistribute of certain metal ions.

References and Further Reading

• Heldin, C., Lu, B., Evans, R., & Gutkind, J. S. (2016). Signals and Receptors. Cold Spring Harbor Perspectives in Biology 8(4). doi:10.1101/cshperspect.a005900.
• Lodish H, Berk A, Zipursky SL, et al. (2000). Receptor Tyrosine Kinases and Ras. Molecular Cell Biology 4th ed. New York: W. H. Freeman; Section 20.4. Available from: https://www.ncbi.nlm.nih.gov/books/NBK21720/.
• Du, Z., & Lovly, C. M. (2018). Mechanisms of receptor tyrosine kinase activation in cancer. Molecular Cancer 17(58). doi:10.1186/w12943-018-0782-4.
• Sever, R., & Glass, C. K. (2013). Signaling by Nuclear Receptors. Cold Spring Harbor Perspectives in Biology 5(3). doi:10.1101/cshperspect.a016709.
• Guan, J., Zhou, W., Hafner, M., et al. (2019). Therapeutic Ligands Antagonize Estrogen Receptor Function by Impairing its Mobility. Cell 178(4); 949-963. doi:10.1016/j.cell.2019.06.026.
• Martin, J., Ales, M. R., & Asuero, A. G. (2018). An overview of ligands of therapeutical interest. Pharmacy & Pharmacology International Journal 6(3); 198-214. doi:10.15406/ppij.2018.06.00177.

Written by

Benedette Cuffari

After completing her Bachelor of Science in Toxicology with two minors in Spanish and Chemistry in 2016, Benedette continued her studies to complete her Master of Science in Toxicology in May of 2018.During graduate school, Benedette investigated the dermatotoxicity of mechlorethamine and bendamustine, which are two nitrogen mustard alkylating agents that are currently used in anticancer therapy.