![In the framework of the 'rotational model', a ligand that binds to the extracellular part of the receptor causes the internal part of the receptor to rotate within the cell membrane, thus essentially regulating the activity inside the cell. In the process, the structural flexibility of the receptors also changes. [Courtesy of Okinawa Institute of Science and Technology, OIST]](https://www.hayadan.org.il/images/content3/2015/11/Rotation-model-illustration1-493x500.jpg)
[Translation by Dr. Nachmani Moshe]
Based on a meta-analysis of more than a hundred studies about cell transmembrane receptors, experts in the field propose a new model for receptor activation - the 'rotational model'. If the model is proven to be correct, the finding will lead to considerable changes in the fields of molecular and cellular biology, biochemistry and the pharmaceutical industry.
"The rotational model, which appears in the current cover issue of the scientific journal BioEssays, represents a significant paradigm shift in the field of cell membrane receptors," said Professor Pierre De Meyts, an expert in the field. Based on a meta-analysis of more than a hundred studies about cell transmembrane receptors, experts in the field propose a new model for receptor activation - the 'rotational model'. If the model is proven to be correct, the finding will lead to significant changes in the fields of molecular and cellular biology, biochemistry and the pharmaceutical industry.
The contents of the biological cells are separated and protected from the external environment by the cell membranes. The survival and reproduction of living things depends on the correct reception and processing of signals from the environment. Receptors located between the cell and the surface of its envelope are proteins integrated into the cell membrane. These proteins are responsible for communication between the cell and its environment. The receptors are proteins with extremely precise roles and respond only to specific molecules, while ignoring all others. Thus, there are many types of receptors; For example, in humans there are over a thousand receptors encoded in the human genome. And yet, the basic activation mechanism is the same for all receptors: a ligand (for example, a hormone, growth factor, cytokine or nutrient) binds to the receptor and initiates changes in the cell's metabolism and activity.
Binding of ligands is a very basic biological process that is essential for all the functions of the living being. Defective functioning of receptors is frequently associated with the development of cancerous tumors and mental and developmental diseases. Therefore, an in-depth understanding of ligand binding is important for drug research and may contribute to the development of better drugs - those that will be in smaller doses, with improved effectiveness and with a reduction in the number and intensity of their side effects. Medicines are essentially molecules that react with receptors and participate in binding ligands while initiating desired responses of the cell. In many cases, drugs mimic the structures and activity of natural ligands, so understanding their activity is important in the field of drug development.
According to the currently accepted model about the activity mechanism of receptors, the 'dimerization' model, before the binding of the ligand, the receptors exist in a monomeric (single unit) form. The binding to the ligand causes the receptors to join together to form a dimer - a functional combination consisting of two similar structural units. The researcher explains: "If the receptors exist in monomeric form, then the situation is dangerous for the cell." Biological cell membranes are not solid at normal body temperature and are more similar in composition to natural oil. Proteins, cholesterol and other substances that make up the membrane materials are free to move along and across. Random collisions of monomeric receptors may activate them, even in the absence of ligands. "However, nature is smart", explains the researcher, "and therefore the receptors must be in the structure of dimers before binding them to the ligand". Indeed, previous studies have shown that active receptors exist in a dimeric form, even in the absence of ligands.
The lead researcher explains that the new model, the 'rotational model', provides an explanation for the activation mechanism of the receptors in their dimeric form by ligands. The researchers examined a number of receptors that had been thoroughly studied in the past, including the Tar, EGFR and BDNF receptors, and came to the conclusion that they all have a similar structure, with and without the ligand. Their transmembrane regions, which extend the length of the cell membrane, probably loop around their long axis, perpendicular to the membrane. A ligand that binds to the outer part of the receptor causes the segment in the receptor located on the inner side of the cell membrane to rotate, and thus, it regulates the activity inside the cell itself. The flexibility of the proteins also changes during the process - before the binding of the ligand, the outer end of the receptor is flexible, while the inner part is less flexible. After the binding of the ligand, the extracellular part loses its flexibility while the intracellular part gains more flexibility. The structural flexibility is driven by thermal energy provided by the body temperature of the living creature. The researchers claim that the rotation of the transmembrane region in the receptors requires a smaller amount of energy than lateral movement of the monomeric receptors within the fluid membrane, as suggested by the dimerization model. The fact that nature tends to "choose" the lowest energy design available to it is another convincing argument for the truth of the proposed model.
