Illustration by Davide Bonazzi

Algorithms stabilize ‘flimsy’ receptors

New computer algorithms are helping to make G-protein coupled receptors more suitable for structural studies.

The trillions of cells in the human body rely on receptors that sit in their cell membranes to communicate with each other. Hundreds of different receptors belong to the G protein-coupled receptor superfamily (called GPCRs for short) and play vital roles in the all organs and bodily systems. Indeed, GPCRs are the targets for almost 40% of therapeutic drugs. As such, deciphering the shape and activity of GPCRs is key to understanding the normal workings of the human biology and could help scientists discover new treatments for various diseases, from depression to high blood pressure to cancer. These receptors, however, are notoriously flimsy and unstable, making them difficult to work with in the laboratory.

Different approaches have been developed to make GPCRs more stable, usually by swapping one or a few of the amino acid building blocks in the protein for other amino acids. Currently, this requires a costly and slow trial-and-error approach in which each amino acid out of 300–400 in the protein is mutated and tested experimentally.

To speed up and reduce the cost of the process, Popov et al. asked if a computer could predict which mutations in the protein would stabilize it, meaning that fewer proteins would actually need to be tested. Four computer algorithms based on four different principles were developed and verified. The first one compares the target GPCR to other closely related receptors, trying to detect variations that cause the instability. The second tries to build in specific stabilizing interactions, or “bridges”, between different parts of the receptor. The third algorithm searches the known structures of other GPCRs for useful mutations. Finally, the fourth one uses accumulated data on the stability of hundreds of mutations in different GPCRs to train a machine learning predictor to recognize stabilizing mutations.

All four algorithms produced useful predictions in a real-life project. Indeed, when combined in one computational tool, named CompoMug, the algorithms made it possible to detect optimal mutations in a human GPCR called 5-HT2C. This made the protein much easier to work with in the laboratory, and ultimately helped to solve its three-dimensional structure (which was reported in a separate study, published earlier in 2018)

The 5-HT2C receptor is involved in regulating, among other things, mood and appetite. Details of its structure might therefore help researchers to design new antidepressants and obesity treatments. Moreover, CompoMug is already helping structural biologists to solve the structures of other GPCRs, which will further facilitate many aspects of GPCR drug discovery.

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