Thursday, November 21, 2024
11/21/2024
Project Summary G protein-coupled receptors (GPCRs) are an important superfamily of seven transmembrane proteins involved in cell-to-cell communication essential for sensing, movement, and thought processes. A significant portion of current approved drug therapies target GPCRs, but suffer from “on-target” side-effects related to the engagement of differential signaling pathways known as “functional selectivity” or “biased signaling.” Exploiting biased signaling represents a promising approach toward designing pathway-selective drugs with better “on- target” profiles, but the mechanisms at the structural level that lead to biased signaling are still poorly understood. Recent advances in structural details of biased ligand recognition have led to the identification of common binding pocket motifs important for `switching' balanced agonists toward biased agonists, and vice versa. Using a structure-based and chemical biology approach, my laboratory aims to use a variety of recently discovered biased ligands to uncover common mechanisms within the binding pocket that govern biased signaling at key GPCR targets. Strategies will incorporate a combination of structure-guided mutagenesis, use of structure-activity relationships (SAR) for recently discovered biased ligands, and high-throughput assays measuring ligand kinetics, G protein dissociation, second messenger production, β-arrestin recruitment, and internalization. This approach focuses on molecular determinants between G protein and β-arrestin-bias agonism at key receptors that have historically shown biased agonist phenomena. Through these studies, a comprehensive mechanistic understanding into GPCR biased signaling will guide researchers toward generations of superior therapeutics. 1
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