Abstract
G-protein-coupled receptors (GPCRs) are a critical family in the human proteome and are involved in various physiological processes. They are also the most important drug target, with approximately 30% of approved drugs acting on such receptors. The members of the family are divided into six classes based on their structural and functional characteristics. Understanding their structural-functional relationships will benefit us in future drug development. In this article, we investigate the features of protein function, structure, and energy that describe the dynamics of the GPCR activation process between different families. GPCRs straddle the cell membrane and transduce signals from outside the membrane into the cell. During the process, the conformational change in GPCRs that is activated by the binding of signal molecules is essential. During the binding process, different types of signal molecules result in different signal transfer efficiencies. Therefore, the GPCR classes show a variety of structures and activation processes. Based on the experimental crystal structures, we modeled the activation process of the β2 adrenergic receptor (β2AR), glucagon receptor (GCGR), and metabotropic glutamate receptor 2 (mGluR2), which represent class A, B, and C GPCRs, respectively. We calculated their activation free-energy landscapes and analyzed the structure-energy-function relationship. The results show a consistent picture of the activation mechanisms between different types of GPCRs. This could also provide us a way to understand other signal transduction proteins.