New High-Resolution Technique for Finding Potential Therapeutic Targets on Proteins in Living Cells

Scientists from Scripps Research have developed a new method to examine how proteins interact with drug-like small molecules in human cells — revealing critical information about how to potentially target them therapeutically.

The strategy uses a combination of chemistry and analytical techniques to reveal the specific places where proteins and small molecules bind together.

The Parker lab aims to discover how proteins function in every human cell type to develop effective therapeutics for a wide range of human diseases.

In this study, Parker and his team built off his initial work in the lab of Scripps Research professor Benjamin Cravatt to create a new method of examining how proteins interact with small molecules in living cells.

They developed an analytical strategy to better understand how these proteins engage with small molecules at much higher resolution than ever before.

To do this, they used chemical probes called photoaffinity probes, which are molecules that can be activated by light to allow the probes to capture a bound protein.

By gathering data from the interactions of proteins with photoaffinity probes, the Parker team identified locations on proteins where small molecules could connect and bind.

Essentially, the team found over a thousand new locks (binding sites on the proteins) and corresponding keys (small molecules), the vast majority of which were new places of small-molecule binding that had not been reported before.

Additionally, they found new features of the binding sites-such as new shapes.

“Identifying these specific binding sites will help scientists design new molecules that fit these pockets even better, potentially leading to more effective therapeutics,” says Jacob M. Wozniak, co-first author, and former postdoctoral fellow in the Parker lab.

Using the wealth of data in this study and collaborating with co-author Stefano Forli, PhD, the authors then modeled how certain molecules might bind to these proteins.

This library of information could be used to design therapeutics that interact with proteins in a more targeted way.

“Our new process reveals additional opportunities for therapeutic intervention and discovery in human cells,” says Parker. “Next, we plan to use this technology to target proteins relevant for autoimmune diseases and cancer.”

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Sources:

Jacob M. Wozniak, Weichao Li, Paolo Governa, Li-Yun Chen, Appaso Jadhav, Ashok Dongre, Stefano Forli, Christopher G. Parker. Enhanced mapping of small-molecule binding sites in cells. Nature Chemical Biology, 2024; DOI: 10.1038/s41589-023-01514-z

Materials provided by Scripps Research Institute. Note: Content may be edited for style and length.

Scripps Research Institute. “New method illuminates druggable sites on proteins.” ScienceDaily. ScienceDaily, 2 January 2024. <www.sciencedaily.com/releases/2024/01/240102151948.htm>.

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