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 need 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 Omics and Ligand Discovery. Shui group is dedicated to developing versatile 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 drug discovery. We develop affinity-selection MS techniques for high-throughput GPCR ligand screening, which generates new ligands to 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 as well as accelerate the discovery of therapeutic targets for the treatment of neurological diseases. In this direction, we are also interested in developing bioinformatics workflows and tools to facilitate functional proteomics data mining.

III. Structural proteomics to probe GPCR conformational dynamics. Despite advances in characterizing GPCR structures and functions, our understanding of receptor activation and signaling is still limited by the lack of information on conformational dynamics. By developing structural proteomics approaches and combining them with structure modeling, we aim to map the conformational ensemble of GPCRs and their signaling complexes in solution or in cells, which could provide new insights into the GPCR activation pathway as well as opportunities for the design of ligands targeting alternative active states of potential therapeutic values.