Cells require the ability to detect and respond to stimuli in their surroundings, including to endogenous metabolites, exogenous nutrients, and environmental irritants. The proteins that are responsible for this process are called chemosensors and are involved in regulating diverse biological processes involved in pain sensation, dietary preference, and metabolic control. Because chemosensors transmit external environmental information into the cell, nearly all chemosensors are structurally-complex membrane proteins that span the cell's plasma membrane multiple times, such as ion channels, transporters, and G protein-coupled receptors. However, because most chemosensors are difficult to express, purify, and solubilize, structural and functional information about them has been exceptionally difficult to obtain. The goal of this Phase 2 proposal is to engineer chemosensors with increased surface expression and increased stability in solution and to map ligand and drug binding sites on these chemosensors.
This project will contribute to human health by providing tools that will enable new small molecules and therapeutic MAbs to be developed against specific chemosensor targets. These targets are involved in the transmission of pain, cancer, and metabolic disorders, yet there are currently no FDA-approved drugs against any of our target protein families. The lack of therapeutic drugs and antibodies against these targets, and most chemosensors in general, reflects their conformational complexity and the lack of tools that have been able to manipulate and engineer these proteins for commercial purposes.
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