CRG builds functional map of beta-2 adrenergic receptor from 7,500 variants, tested in human cells

Researchers at the Centre for Genomic Regulation (CRG) have developed a method for building detailed functional maps of G protein-coupled receptors (GPCRs), a protein family on the cell surface, according to eurekalert.org. The study was led by Taylor Mighell and Ben Lehner and published in Nature Structural & Molecular Biology. The work was done on human cells and is at the research stage. eurekalert.orgeurekalert.orgeurekalert.orgOpen source ↗

One in three regulatory-approved drugs worldwide targets this family. There are 800 types of GPCRs; adrenaline, histamine and serotonin each rely on different variants to pass signals into the cell. Beta blockers, antihistamines, opioids and asthma inhalers act on them.

The receptors have similar architecture, so a drug designed for one often binds others and causes unwanted side effects. According to the authors, designing a drug that reliably prefers one receptor over another has been largely a matter of luck.

How the map was built

The team mapped the beta-2 adrenergic receptor, which signals cells to relax airways and is a target of asthma and COPD inhalers such as salbutamol and salmeterol. They created thousands of protein variants by swapping one building block for another. In total, 7,500 versions were synthesised. eurekalert.orgeurekalert.orgeurekalert.orgOpen source ↗

Each variant was placed in a human cell and tested with different drug doses and other parameters. This produced more than 150,000 measurements for a single receptor.

Hidden sites and a second receptor

The data showed potential drug targets that had been previously hidden. Many of these regions have adjustable positions that can be altered to finetune receptor behaviour, which could allow more precise control of the cellular response.

To check that the method works beyond one receptor, the team applied it to a second protein involved in regulating water in the kidneys and found comparable results. The team's long-term ambition is to build similar maps for many more GPCR family members. eurekalert.orgeurekalert.orgeurekalert.orgOpen source ↗

The authors describe the work as the start of a third era of GPCR drug discovery. The first era screened thousands of compounds with little understanding of why they worked; salmeterol, developed in the 1980s, targets a region that the new map predicts is important. The second, from the 1990s, designed drugs from the receptor's three-dimensional structure and earned a Nobel Prize in 2012, but could not predict what a drug does after binding.

The new method links the structure and function of each part of the receptor. In the words of Dr. Mighell: "Now, we have something closer to a manual than a diagram."