Presentation Type
Poster
Faculty Mentor’s Full Name
Travis Hughes
Faculty Mentor’s Department
Biomedical and Pharmaceutical Sciences
Abstract / Artist's Statement
Farnesoid X receptor (FXR), also known as bile acid receptor, is a metabolic nuclear receptor protein that controls gene expression in glucose, amino acid, lipid, and bile acid metabolism. FXR is a transcription factor that alters gene expression upon ligand binding through recruitment of coregulators. It is a primary drug target for nonalcoholic steatohepatitis (NASH) and primary biliary cholangitis (PBC). FXR binds a wide variety of ligands, many of which do not resemble the endogenous bile acids that FXR binds, suggesting that it can be activated by a wide variety of ligand scaffolds. However, the effect ligands have on the surfaces of FXR that bind other proteins remains poorly understood. Because ligands create physiological effects by altering these surfaces understanding ligand-surface structure relationships is important to drug development. Here, we use fluorine NMR to show how the conformational ensemble of the FXR coregulator binding surface and the heterodimerization surface changes when different ligands are bound. We show that agonists stabilize helix 12, an essential part of coactivation binding to FXR, and helix 11, which encompasses the heterodimerization surface necessary for FXR to bind RXRα. Our work uses a highly sensitive technique to define the active conformations of FXR, revealing that FXR dynamics are more complex than suggested by a two-state “mousetrap” model of agonism.
Category
Physical Sciences
More than a mousetrap: conformational differences in FXR agonism as seen by fluorine NMR
UC South Ballroom
Farnesoid X receptor (FXR), also known as bile acid receptor, is a metabolic nuclear receptor protein that controls gene expression in glucose, amino acid, lipid, and bile acid metabolism. FXR is a transcription factor that alters gene expression upon ligand binding through recruitment of coregulators. It is a primary drug target for nonalcoholic steatohepatitis (NASH) and primary biliary cholangitis (PBC). FXR binds a wide variety of ligands, many of which do not resemble the endogenous bile acids that FXR binds, suggesting that it can be activated by a wide variety of ligand scaffolds. However, the effect ligands have on the surfaces of FXR that bind other proteins remains poorly understood. Because ligands create physiological effects by altering these surfaces understanding ligand-surface structure relationships is important to drug development. Here, we use fluorine NMR to show how the conformational ensemble of the FXR coregulator binding surface and the heterodimerization surface changes when different ligands are bound. We show that agonists stabilize helix 12, an essential part of coactivation binding to FXR, and helix 11, which encompasses the heterodimerization surface necessary for FXR to bind RXRα. Our work uses a highly sensitive technique to define the active conformations of FXR, revealing that FXR dynamics are more complex than suggested by a two-state “mousetrap” model of agonism.