The cover image for the April 4 issue of Biophysical Journal shows the human Smoothened (SMO) receptor from the class F subfamily of G-protein coupled receptors. It acts as a molecular telephone, sitting at the junction of a cell and its environment, and transfers signals from outside the cell to the inside. The image, rendered by using the 3D modeling software Blender, showcases the SMO protein undergoing activation.
In our computational study, we explain the protein’s activation process. In essence, activation is a series of conformational (shape) changes that the SMO receptor undergoes to be able to transfer signals. The activation process is triggered by SMO receptor binding to an agonist, a molecule responsible for triggering SMO receptor activation. Once the SMO receptor reaches an active state, it can bind to proteins inside the cells called “G-proteins,” thus completing the process of transferring the signal from the outside of the cell to the inside. In our study, we observe that the SMO receptor’s activation in the presence of an SMO agonist (red) triggers the opening of a tunnel (illuminated) inside the protein. One of the leading hypotheses related to the SMO receptor’s endogenous activation involves the transport of a cholesterol molecule from the membrane to the binding site. This tunnel opening hence provides further corroboration to the cholesterol-transport–like activity of the SMO receptor.
In our day-to-day lives, the SMO receptor plays an integral role in maintaining our general well-being, because it is responsible for transferring signals related to cell division and differentiation, making it a crucial carrier of information for maintaining homeostasis. If the SMO receptor is under- or over-stimulated, it can cause birth defects in the developing embryo and cancer in adults. Hence, an SMO protein that functions optimally is vital for healthy life. Studying the activation process of proteins like SMO is thus essential, because it can provide us with critical insights for designing better and more specific drugs that can target SMO more effectively. SMO antagonists have been designed to treat basal cell carcinoma and pediatric medulloblastoma. Our research group works on understanding the role of dynamics in protein structure and function. You can learn more about our research on our group website (https://www.shuklagroup.org).
— Prateek D. Bansal, Soumajit Dutta, and Diwakar Shukla