The Nature of Functional Features of Different Classes of G-Protein-Coupled Receptors

SIMPLE SUMMARY: The sequence–structure–function paradigm, which emphasizes the relationship between the 3D structure and functions of a protein, is a core concept in biology. The relationship further determines the functional specificity of proteins. By studying G-protein-coupled receptors (GPCRs), we investigated how the 3D structures of proteins are related to the activation mechanisms and functions. The activation of GPCRs involves many events, such as conformational changes, agonist binding, G-protein binding, nucleotide binding/release, etc. By exploring the coupled free-energy landscape of these events, we offer a possible explanation for the functional differences between the three families of GPCRs and how they are related to their signal responding specificities. 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.