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Ye Lab@
Department of Molecular Biosciences
Conformation, Dynamics, and Signal Transduction of GPCR
1. Methodological Innovation
We are developing NMR spectroscopic and biological tools to map and quantify the conformational landscape of membrane proteins such as GPCRs. These breakthroughs enable us to study the roles of individual conformational states, their transitions, and dynamics, and thus, the impacts on signaling efficacies and biases. Our ultimate goal is to create precise medications that target a specific disease-related conformation, rather than the entire protein, with minimal side effects.
2. GPCR and Diseases
We study a set of disease-related GPCRs to understand their activations using BRET, cryo-EM, and MD simulation, complemented by our primary tool, 19F-qNMR, for better drug development. We're currently concentrating on GPCRs linked to neurological, cardiovascular, and obesity-related diseases, including adenosine receptors, opioid receptors, GLP-1R/GCGR receptors, PAC1R, and adenylyl cyclases.
GPCRs constitute the largest transmembrane protein family, with more than 800 members. They serve as gatekeepers, controlling transduction for various physiological and pathogenic signals, and are involved in almost every aspect of physiological activities in our human body. It is, therefore, easy to imagine that any GPCR signaling dysfunction probably leads to a disease such as cancer, cardiac failure, neurological disease, infection, obesity, inflammation etc. Although only 10% of GPCRs have been subjected to drug discovery, they are already targeted by nearly 35% of FDA-approved medications, indicating a continued tremendous potential in drug discovery.
3. GPCR, Ecosystem, and Public Health
We also study a set of dinoflagellate GPCRs related to the occurrence of red tide blooms. Our vision for this line of research is to unravel the role of GPCRs in the bioluminescent signaling process. Our goal includes exploring tools in modulating dinoflagellate bioluminescence that often damages coastal ecosystems and causes public health concerns after consuming seafood contaminated by red tide algae. We also aim to understand the evolutionary role of unicellular GPCRs. Towards this, most recently, we identified the first wave-sensitive receptor that illuminates the ocean at night, named as BIR1.
4. New Drug development of q-CAR Paradigm
With advances in technology for quantitatively delineating a protein's conformational landscape in response to ligand binding, mutation, and signaling partners, we proposed a new concept of quantitative conformation-activity relationship (q-CAR) for drug discovery as a paradigm shift for future medication targeting disease-related conformational dynamics. The core concept extends traditional QSAR by focusing on protein dynamics and conformational transitions rather than static molecular structures, as "no motion, no function." Recent progress in Bio-NMR and AI tools makes this feasible to pursue in the future.
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