G protein-coupled receptors (GPCRs) form the largest family of cell surface receptors in the human genome, playing a pivotal role in various cellular and physiological pathways. Their significance as drug targets has led to extensive research, with a focus on their interaction with two transducers: heterotrimeric G proteins and β-arrestins (βarr). Conventionally, it is believed that only fully-engaged GPCR-βarr complexes are functionally competent. However, my PhD work challenges this conventional notion, revealing that partially-engaged complexes can mediate receptor endocytosis and downstream signaling.

Furthermore, I've identified and characterized exclusive βarr-coupled seven transmembrane receptors, unraveling their downstream signaling pathways through unbiased screens. Additionally, I've designed synthetic antibody fragments allowing the monitoring of GPCR-βarr trafficking inside cells with spatio-temporal resolution, overcoming limitations inherent in other assays and reporter systems. These sensors unveil structural and functional diversity in GPCR-β-arr complexes, highlighting intricate fine-tuning mechanisms directing receptor-specific signaling responses.

In my postdoctoral research, I've shifted focus to the structural elucidation of GPCR-G-protein activation and signaling, particularly examining FFAR1. This GPCR responds to circulating free fatty acids, enhancing glucose-stimulated insulin secretion. Cryo-electron microscopy has been employed to reveal the structural basis of FFAR1 activation by endogenous fatty acids and synthetic agonists. These structures demonstrate how FFAR1 functions without the highly conserved ‘DRY’ and ‘NPXXY’ motifs of Class A GPCRs, showcasing how membrane-embedded drugs can bypass the orthosteric site to fully activate G protein signaling.

In summary, my work provides crucial insights into GPCR-G-protein and GPCR-βarr interactions, offering implications for biased agonism and the development of improved therapeutics.