This project seeks to understand G protein inhibition in the treatment of uveal melanoma and other Gq-related diseases. The heterotrimeric G proteins are molecular switches regulate biological functions like sight, smell, and memory. This pivotal role makes G proteins essential players in physiology and pathophysiology. However, when G proteins mutate, they result in a variety of diseases from cancer to heart disease. For example, a single mutation in the Gq protein is known to cause uveal melanoma, a cancer in the iris of our eyes that remains largely untreatable short of removing the eye. This is due to an over-active Gq protein. Thus, targeting over-active Gq mutants presents a unique opportunity to treat disease.
Natural product chemistry offers the chance to identify treatments against these difficult to treat targets. A peptide found in Christmas berries, YM-254890 (YM) binds and inhibits Gq, preventing the over-active from resulting cancers. Previous results suggest that YM is even useful in cellular and animal models. However, both the mechanism of Gq inhibition as well as how to optimize YM further (for simplicity, potency, or specificity) remain unknown. This project simulates the heterotrimeric Gq protein bound to YM, to understand its mechanism. Project 16446 simulates the Gq protein by itself, which will help us understand its behavior in the cell.
List of Contributors
This project is managed by Sukrit Singh at Washington University in St. Louis.
Sukrit Singh is a Biophysics PhD student in Greg Bowman's lab at Washington University in St. Louis.
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