Structural Determinants of Biologic Recognition Across GPCR Classes

Abstract

The rapid increase in experimentally resolved G protein-coupled receptor (GPCR)–biologic complexes has substantially improved our understanding of the molecular basis of receptor recognition and modulation. However, despite the growing number of available structures, a comparative framework integrating the major GPCR classes is still lacking. In this review, we analysed experimentally resolved GPCR–biologic complexes across receptor Classes A, B, C, and F to identify the structural principles governing biologic recognition. Our analysis shows that the architecture of each GPCR class shapes distinct recognition paradigms, while two interdependent structural variables emerge across the superfamily: the accessibility and organization of receptor surfaces and the conformational states associated with these regions. Class A receptors primarily expose compact extracellular surfaces, Class B receptors exploit large extracellular domains that support modular ligand recognition, whereas Class C and Class F receptors rely on structured extracellular domains (Venus Flytrap and cysteine-rich domains, respectively) that enable conformational selection and allosteric regulation. Together, these observations establish a structural framework linking receptor accessibility and conformational dynamics to biologic recognition and pharmacological modulation. This framework provides a conceptual foundation for the rational design of next-generation GPCR-targeted biologics with improved selectivity, efficacy, and functional precision.