Developed a method for mapping cell receptors that regulate inhibitory reactions

Developers of drug therapies have been searching for long-term drugs that are able to access cell receptors that regulate 'stress-suppressive reactions' in the human body, but do not yet have a molecular type. Small ones bring success to them. To date, a research team at the Salk Institute has demonstrated the way a new tool is used to map binding areas on these receptors, which enables the development of therapies. effective treatment.

In the online international journal Angewandte Chemie , the researchers developed a method to determine how unnatural amino acids (unnatural amino acids, Uaas, artificial amino acids) can be used to map structures. Structure of a receptor of corticotropin release hormone ( CRF-R1 ). They also showed how this new tool supports locating three regions on this receptor, enabling peptide hormones to act to activate or inhibit the receptor. Many binding areas for other natural ligands are also predicted to be on this receptor.

'This receptor is very important in regulating the stress response in humans, no one knows how it binds correctly on the cell carrier, this is the key to understanding how it functions and can is operated in therapy, 'Gs. Irene Coin said. ' We have created a method that provides a new perspective on how peptides interact with this receptor .'

Illustration of receptors on the cell surface.

Not only useful for understanding the specific function of CRF-R1, this method may be appropriate to map the interactions of receptors associated with G-proteins (G-protein-coupled receptors, GPCRs). , a large protein family in which CRF-R1 is a member.

There are hundreds of GPCRs in the human body, and they are the molecular target of more than 30% of today's pharmaceuticals, Gs. Wang said. ' This technique has a great potential to assist in answering basic biological questions related to various classes of GPCRs, and to guide the development of highly specific drugs in specific treatment cases . '

This research stems from the basic discoveries of the Salk Research Institute. The first was the discovery in 1981, creating a CRF receptor stream. This receptor binds to corticotropin release hormone, which regulates endocrine, animal, and immune responses to stress.

The tool that researchers use consists of three different molecules. A molecule is RNA (tRNA) that transports amino acids to protein synthesis. The second molecule is an enzyme synthetase (synthetic enzyme that requires ATP participation) to identify tRNA, and combine it with a third molecule - an artificial amino acid . These amino acids are chemically different from 20 natural amino acids that exist in the body; they can be modified to have desired properties, such as the ability to glow or create a chemical reaction when exposed to light.

Because of knowing the amino acid sequences on CRF-R1, the researchers repaired some specific areas of DNA that they thought might be close to the ligand binding area. The corrected tRNA and synthetase work together to attach this artificial amino acid to those regions. ' We can control the positions where amino acids come in, and we put them in a position where we think it's an attachment, based on some other data, ' Gs. Coin said. 'After attaching radioactive ligands to cells with these receptors, the scientists shone light, activating the artificial amino acid to hold the ligand if the second ligand approached .'

In this way, mutants that carry an artificial amino acid in another location on the receptor can be repaired.'This is a way to map the surface of this receptor to see which positions are close to the ligand,' Gs. Coin said.

And other ligands can attach to other positions on the receptor, so this technique can be used to build a complete map of ligand-specific binding sites on receptors, Gs. Wang said. With this knowledge, pharmaceuticals are formatted to attach specifically to the target mounting position.

Researching 12 different sites on the receptor, the scientists found three regions with a large ligand. ' We have published a basic method and map of attached areas. Other ligands show another type of attachment . "