The superfamily of G-protein-coupled receptors (GPCRs) play essential roles in various pathophysiological conditions and represent a prominent family of therapeutic targets which 30-40% of marketed drugs act on. Innumerable efforts have been made to identify novel ligands that can modulate the activity of specific GPCRs and characterize GPCR-ligand interactions at the molecular level. However, the limitations of most commonly used techniques for GPCR ligand screen and global proteomics highlight the needs for more sensitive, selective and robust technologies that can accelerate GPCR drug discovery and functional study.

The central theme of Shui group research is GPCR Chemical Biology and Proteomics. Shui group is dedicated to developing chemical probes and mass spectrometry (MS)-based approaches to be integrated with biochemical, structural, pharmacological and computational approaches for GPCR research in three specific directions:

I. GPCR ligand screening and chemical tool discovery. We develop affinity-selection MS techniques for high-throughput GPCR ligand screening from synthetic libraries or natural herb extracts. This allows us to discover a series of new-scaffold bioactive ligands which can serve as chemical tools/probes for elucidating GPCR signaling mechanisms or as potential leads for drug development.

II. Functional proteomics targeting GPCR proteins in the brain. Through profiling the transmembrane proteome, especially the GPCR superfamily, in the brain with advanced proteomics technology, we aim to expand the understanding of transmembrane protein organization and regulation in the central nervous system, which would inspire the discovery of therapeutic targets for the treatment of neurological diseases. In this direction, we are also interested in developing bioinformatics frameworks and tools to facilitate functional proteomics data mining.

III. Structural proteomics to probe GPCR conformational dynamics. Despite advances in revealing GPCR structures and functions, our understanding of receptor activation and signaling is still limited by incomplete knowledge of conformational dynamics. By developing structural MS and proteomics approaches, we aim to characterize the conformational ensemble and dynamics of GPCR complexes in solution and in intact cells or tissues, which could provide new insights into GPCR activation and regulation in a near-physiological context.