Poster abstracts

Poster number 36 submitted by Berkay Selcuk

Molecular basis of receptor divergence in GPCR superfamily

Berkay Selcuk (Biophysics Graduate Program, The Ohio State University, US), Igor Jouline (Department of Microbiology and Translational Data Analytics Institute, The Ohio State University, US), Ogn Adebali ( Molecular Biology, Genetics and Bioengineering Program, Faculty of Engineering and Natural Sciences, Sabanci University, Istanbul, Turkey)

Abstract:
G protein-coupled receptors (GPCRs) are integral membrane proteins that orchestrate a wide range of physiological processes, enabling organisms to sense and respond to diverse environmental signals. The human genome contains over 800 GPCRs classified into seven subfamilies (classes A, B1, B2, C, F, T, and olfactory), each shaped by distinct evolutionary trajectories. Because previous studies have predominantly focused on the evolution of specific receptor subsets or limited functional aspects, our understanding remains incomplete regarding how individual receptors preserve their core functions while acquiring novel ligand binding and signaling profiles. In this study, we systematically identified subfamily-wide conserved residues and categorized them as “common residues” responsible for subfamily-wide common functions, and “selective residues” responsible for functional specialization of receptors within a subfamily. Structural mapping of SRs revealed that classes A, B1, F, C and olfactory receptors exhibit high selectivity for ligand binding, while classes A and B2 exhibit high selectivity for G protein coupling. In contrast, CRs highlight subfamily-specific adaptations such as extracellular arrangement in olfactory receptors and ICL2 in class T, and shared features across multiple subfamilies such as cholesterol binding, disulfide bridge, toggle switch and several prolines. Together, these findings offer an evolution-driven understanding on GPCR functionality, providing the molecular mechanism underlying GPCR divergence driven by changes in SRs. This evolutionary understanding can be translated into the design of highly selective drugs and the engineering of artificial receptor subtypes with novel ligand binding and G protein coupling capabilities.

Keywords: GPCR, evolution, selectivity