Structure and mechanism
Membrane proteins constitute about 25% of the animal proteome and orchestrate essential life processes like body formation and brain function. While many membrane proteins emerge as potential therapeutic targets, drug development has not been able to meet the desperate need. Major impediments in finding novel drugs targeting membrane proteins stem from the lack of mechanistic understanding of how those important proteins function. Our research team aims to unveil structures of eukaryotic membrane proteins and elucidate the mechanisms underlying their function, modulation, and regulation. We are particularly interested in membrane proteins that regulate extracellular ATP mediated signaling, an important mode of cell-to-cell communication that mediates immune responses and neurotransmission. We use multidisciplinary techniques including cryo-EM, X-ray crystallography, electrophysiology, and functional reconstitution.
Cryo-EM structure of pannexin1
The P2X7 receptor is a non-selective cation channel activated by extracellular ATP. Chronic activation of P2X7 underlies many health problems such as chronic pain, yet we lack effective antagonists due to poorly understood mechanisms of inhibition. We obtained the first crystal structures of a mammalian P2X7 receptor in the presence of five structurally different drugs. We discovered a new drug-binding pocket and a unique turret-like structure in the P2X7 receptor, both of which seem to narrow after ATP-binding. We propose that these unique structural rearrangements account for the subtype-specific action of the P2X7 drugs.
Physiology and behavior
We conduct research on the physiology and behavior of membrane proteins utilizing a transparent roundworm, Caenorhabditis elegans. This remarkable model organism consists of approximately 1000 cells, yet it possesses finely regulated cell-to-cell communication, allowing for the manifestation of complex behaviors. With many essential genes and conserved genetic pathways, C. elegans serves as an exceptional model system for exploring the role of membrane proteins in physiological processes and behavior.
Basal slowing response of TTY k/o worms
We employ CRISPR-Cas9 genome editing to create knock-in and knock-out worms, providing us with valuable tools to bridge the gap between structural/mechanistic information and physiological function. Our research approach integrates cell biology, biochemistry, proteomics, and behavioral studies to comprehensively explore the in vivo roles of membrane proteins.
Pain management is central to human and veterinary medicine. However, pain is a subjective experience, making it challenging to properly assess the source, type, and the degree of pain for effective treatment. This difficulty is particularly prominent in pediatric patients and animals, where pain scale are often prone to under- or overestimation. By leveraging cutting-edge technology and interdisciplinary expertise, our team aims to create a painometer that can revolutionize pain assessment in medical and veterinary settings. This biosensor will help clinicians and caregivers accurately gauge the extent of pain experienced by patients and animals, allowing for more effective and targeted pain management strategies.
Pannexin1 is a potential biosensor for pain