G-protein-coupled receptors (GPCRs) serve as critical drug targets, and understanding their structure-function relationship is paramount. The sequence-structure-function paradigm emphasizes the relationship between the three-dimensional structure and function of proteins, constituting a core concept in biology. This relationship further determines the functional specificity of proteins. Through the study of G-protein-coupled receptors (GPCRs), we have investigated the relationship between the three-dimensional structure of proteins and their activation mechanisms and functions. GPCR activation involves numerous events such as conformational changes, agonist binding, G-protein binding, nucleotide binding/release, and more. By exploring the coupling of these events and changes in free energy, we offer a possible explanation for the functional differences among the three classes of GPCRs and their relationship to signal response specificity.