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New Insights Could Mean Longer-Lasting Drugs with Less Side Effects

Lists of possible drug side effects can be lengthy and worrisome, and sometimes side effects create problems that need to be treated with yet more pharmaceuticals. Scientists are looking for ways to remedy this, including creating drugs that take more precise action in the body.

A new paper published in Nature Structural and Molecular Biology could help researchers on this quest. Authors on the paper include Professor Amédée des Georges of the Advanced Science Research Center at The Graduate Center, CUNY, and The City College of New York, as well as Danya Ben-Hail and Fadi Samaan of the ASRC.

The study examines the relationship of proteins called G protein-coupled receptors, or GPCRs, with other proteins called Beta-arrestin and G protein, all of which reside in the human cell. GPCRs constitute a huge family of proteins that are involved in many different processes, from taste to mood regulation, as well as the immune system and inflammation. Because of this, GPCRs are very important drug targets.

The new research was co-led by Robert Lefkowitz of Duke University, who in 2012 won the Nobel Prize in chemistry for contributing to our understanding of how GPCRs work. Now, the researchers teamed up to explain a recently observed phenomenon—GPCRs continuing to signal with G proteins after binding to Beta-arrestin. The binding action was previously thought to stop this signaling.

Using cryo-electron microscopy, the scientists were able to take an up-close look at why this happens, by observing how the proteins are arranged and bound together. With a better understanding of the proteins’ structure and conformation, the scientists hope drug developers can make molecules that only trigger GPCRs in the right way for the right amount of time, thus reducing side effects.

“This has been a very exciting project from the start,” des Georges told The Graduate Center, “pushing the boundaries of cryo-electron microscopy to answer a fundamental question in biology that has important implications for medicine.”

Beyond SUM

Explore This Work

Structure of an endosomal signaling GPCR–G protein–β-arrestin megacomplex
Nature Structural & Molecular Biology , 2019

Work By

Amédée des Georges (Assistant Professor, Chemistry, Biochemistry) | Profile 1