Receptors are proteins that are responsible for cell signaling and can be classified by their location and response. Receptor stability is of great significance due to the way in which receptors specifically bind with ligands to create a response, and their role in each biochemical pathway. If the precious balance of stability is not maintained, alterations in the structure of receptors may occur, causing many diseases and physiological disorders.
Receptor Structure and Mechanisms of Action
A receptor is a complex protein that binds chemical signals from outside of a cell. This binding consequently causes a conformational change in the receptor, which then triggers a signaling cascade (1). This allows cellular responses to be coordinated at a molecular level, often causing changes in the transcription or translation of genes that is followed by post-translational and conformational changes in the protein. Such molecular responses can also control cell growth, proliferation, metabolism, and many other processes.
The molecules that endogenously bind to a receptor are known as ligands and are as diverse as their receptors. A ligand can be a protein, neurotransmitter, hormone, or other small molecule (2). Each receptor is linked to a certain biochemical network, and when a specific ligand binds to the extracellular domain of the receptor, it inhibits or activates the receptor’s associated interactome, causing a biological response (3). This reversible binding occurs by intermolecular forces such as ionic bonds or hydrogen bonds, which determine a measurable and quantifiable affinity between the ligand and the receptor.
There are two types of receptors: Intracellular receptors, which include cytoplasmic and nuclear receptors that can be found inside the cell, and transmembrane receptors, which can be found within the cell membrane. These are further classified into ion channel-linked receptors, G protein-linked hormone receptors, and enzyme-linked hormone receptors (2).
Intracellular receptors generally affect gene expression through the signaling cascade that triggers DNA transcription (2). Transmembrane receptors are involved in the cell response. Within this category, ion channel-linked receptors interact with fast neurotransmitters such as acetylcholine, an activation that causes the opening or closing of ion channel pores and changes in the membrane potential of the target cell (2). G protein-linked hormone receptors regulate intracellular reactions by binding to hormones and slow transmitters such as dopamine (2). Meanwhile enzyme-linked hormone receptors are often protein kinases; the intracellular domain of these receptors is an enzyme whose catalytic activity is regulated by the interaction of the extracellular signal and the receptor (2).
Measurement of Receptor Activity and Signaling Pathways
Interaction between different signaling pathways permits cellular activity and is required to carry out all of the physiological processes in our bodies (1). Stability of the quaternary structure of the protein, therefore, is crucial to molecules performing their roles.
Technology employed to measure protein stability can be used to determine receptor unfolding that can lead to a decrease in the affinity of the ligand to the receptor or the non-functionality of the receptor. This has the potential to cause many physiological disorders and often leads to disease. Many palliative treatments include therapies with ligands (4).
The pharmaceutical industry is using complex modern techniques to develop drugs that operate as ligands with high affinity for specific receptors. The research done is of great interest for disease treatment related to altered biological pathways, which are due to hereditary defects in receptor genes or reduction in the synthesis of the ligand (5)
After many years of research, therapies have finally become more effective and treatments now involve better drugs that improve receptor stability. Undoubtedly, there has been a major improvement in the quality of life for many patients with cancer and diverse neurological diseases that even 10 years ago would have felt like a distant dream.
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- Arimont M, Sun S, Leurs R, Smit M, J P de Esch I, de Graaf C. Structural Analysis of Chemokine Receptor–Ligand Interactions. J Med Chem. 2017 Jun 22; 60(12): 4735–4779. Published online 2017 Feb 6. doi: 10.1021/acs.jmedchem.6b01309
- Borroto A, et al. First-in-class inhibitor of the T cell receptor for the treatment of autoimmune diseases. Sci Transl Med. 2016 Dec 21;8(370):370ra184. doi: 10.1126/scitranslmed.aaf2140.
- Reinert T, Barrios C. Optimal management of hormone receptor positive metastatic breast cancer in 2016. Ther Adv Med Oncol. 2015 Nov; 7(6): 304–320. doi: 10.1177/1758834015608993