Structural Determinants of Biologic Recognition Across GPCR Classes
- 1Department of Pharmacy, University of Naples “Federico II”, Via D. Montesano, 49, I-80131 Naples, Italy
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.
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BibTeX
@article{fiorillo2026structural,
title = {{Structural Determinants of Biologic Recognition Across GPCR Classes}},
author = {Bianca Fiorillo and Alessandra Guarracino and Oriana Vitale and Federica Moraca and Bruno Catalanotti},
journal = {Cells},
year = {2026},
month = oct,
doi = {10.3390/cells15211958},
url = {https://www.mdpi.com/2073-4409/15/21/1958},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Structural Determinants of Biologic Recognition Across GPCR Classes
AU - Bianca Fiorillo
AU - Alessandra Guarracino
AU - Oriana Vitale
AU - Federica Moraca
AU - Bruno Catalanotti
PY - 2026
DA - 2026/10/28
JO - Cells
DO - 10.3390/cells15211958
UR - https://www.mdpi.com/2073-4409/15/21/1958
AB - 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.
SN - 2073-4409
ER -