Capturing the Opioid Receptor in Motion
Research led by a doctoral student in Associate Professor Rajan Lamichhane’s lab could point the way for discovering how opioid drugs produce distinct functional effects.
The μ-opioid receptor is one of the most important targets in pain medicine and opioid drug development. Like many membrane proteins, however, it is difficult to investigate using biophysical approaches outside the cell membrane. Although detergents are commonly used to solubilize membrane proteins for structural and biophysical studies, they can alter the proteins’ native environment, making it challenging to determine how the receptor naturally moves and changes shape during activation.
Eugene Agyemang (PhD ’26) in the Lamichhane Lab led a collaborative study exploring the structure and motions of an engineered, water-soluble variant of the human μ-opioid receptor with researchers at Oak Ridge National Laboratory (ORNL) and the Perelman School of Medicine at the University of Pennsylvania. The engineered receptor, developed at Penn, served as the foundation for this work by making it possible to investigate receptor dynamics in solution without the surrounding lipid membrane.
Building on this unique platform, the collaboration combined custom-built single-molecule fluorescence instrumentation in the Lamichhane Lab with neutron scattering experiments at ORNL to investigate the receptor’s structure and dynamics across different spatial and timescales. The work was recently published in the Journal of Biological Chemistry.
The team found that the μ-opioid receptor is intrinsically dynamic, sampling multiple structural states even in the absence of its native membrane environment. Ligand binding shifted the balance among these states and altered the receptor’s internal motions. These findings show that important aspects of receptor dynamics are inherent to the receptor itself and can be studied outside the membrane, providing insight into activation that cannot be captured by static structures alone.
This new perspective on receptor dynamics has broader implications for opioid and G protein-coupled receptor (GPCR) research. Rather than focusing only on the structure of a receptor bound to a specific drug, researchers can use this system to examine how different ligands reshape the receptor’s dynamic landscape and how those changes relate to signaling. The approach could, therefore, provide a new way to study how opioid drugs produce distinct functional effects.
The work has already attracted interest from the broader membrane protein community. Agyemang was invited to present findings from the study at a membrane protein conference organized by the SMALP Network, an international community developing new approaches for studying membrane proteins. The approach provides a unique experimental framework for investigating how receptor dynamics contribute to opioid signaling and may also be applicable to other challenging GPCRs.