19F NMR: A promising tool for dynamic conformational studies of G protein-coupled receptors.

Advances in X-ray crystallography and cryoelectron microscopy enabled unprecedented insights into the activation processes of G protein-coupled receptors (GPCRs). However, these static receptor structures provide limited information about dynamics and conformational transitions that play pivotal roles in mediating signaling diversity through the multifaceted interactions between ligands, receptors, and transducers. Developing NMR approaches to probe the dynamics of conformational transitions will push the frontier of receptor science toward a more comprehensive understanding of these signaling processes. Although much progress has been made during the last decades, it remains challenging to delineate receptor conformational states and interrogate the functions of the individual states at a quantitative level. Here we cover the progress of 19F NMR applications in GPCR conformational and dynamic studies during the past 20 years. Current challenges and limitations of 19F NMR for studying GPCR dynamics are also discussed, along with experimental strategies that will drive this field forward.

The Potential of 19F NMR Application in GPCR Biased Drug Discovery.

Although structure-based virtual drug discovery is revolutionizing the conventional high-throughput cell-based screening system, its limitation is obvious, together with other critical challenges. In particular, the resolved static snapshots fail to represent a full free-energy landscape due to homogenization in structural determination processing. The loss of conformational heterogeneity and related functional diversity emphasize the necessity of developing an approach that can fill this space. In this regard, NMR holds undeniable potential. However, outstanding questions regarding the NMR application remain. This review summarizes the limitations of current drug discovery and explores the potential of 19F NMR in establishing a conformation-guided drug screening system, advancing the cell- and structure-based discovery strategy for G protein-coupled receptor (GPCR) biased drug screening.