Research in the Che lab is aimed at comprehensively characterizing and dissecting the molecular mechanisms of opioid receptor signaling. The goal is to gain an atomic-level understanding of opioid receptor activation, and to use this information to develop chemical and synthetic biologic tools (e.g., nanobodies) to ultimately lead to the development of safer, non-addictive pain medications. Che’s work will integrate structural (e.g., X-ray, Cryo-EM) and pharmacological approaches, and leverage these data to generate subtype-specific novel chemicals as in vivo precision pharmacology probes to understand opioid receptor signaling spatiotemporally. These will be useful probes to interrogate signaling pathways and provide a platform for the discovery of new chemical and biological matter for potential therapeutic applications.
Structure and function of pain-related G protein-coupled receptors
Pain sensation, like other neuronal activities, rarely involves just a single target. However, the primary focus is on the opioid receptors because of their undisputed roles in pain management. Medications targeting opioid receptors are associated with exceptionally high abuse potentials and often cause fatal side effects. Several other receptors have also been implicated in mediating pain sensation at different levels, but their pharmacology remains poorly understood. We will combine x-ray crystallography, cryoEM, and pharmacological approaches to understand ligand selectivity and receptor activation, which provides a route for discovering alternatives to opioids.
Dissecting the molecular determinant of opioid receptor signaling
GPCR activation leads to the coupling of intracellular transducers and regulators. This process is ligand-specific. Drugs for any given receptor thus may preferentially activate a spectrum of signaling pathways, such as G protein-dependent (e.g., Gs, Gq, Gi) or G protein-independent (e.g., beta-arrestin1/2, GRKs). Understanding the molecular mechanism behind these pathways and whether or how they correlate with a unique behavioral response will be beneficial for the design of safer therapeutics.
