The application of unnatural amino acids to chemokine receptor research

Recent reports of G protein-coupled receptor (GPCR) X-ray structures, including the structure of CXCR4 chemokine receptor, have advanced the aim of elucidating with chemical precision GPCR ligand binding, activation and interactions. Structure-based drug design is also becoming increasingly important as a tool to find new GPCR-targeted drugs. As new structural information becomes available, complementary experimental strategies are required to address questions related to receptor dynamics and organization in membranes. To this end, the introduction of unnatural amino acids (UAAs) into GPCR ligands and expressed receptors has opened up new opportunities to study GPCRs in native systems. Because UAAs can contain a wide range of chemically diverse functional groups, genetic incorporation of UAAs into proteins provides an important new tool of chemical biology to the study of GPCRs, including chemokine receptors. For example, UAAs enable the incorporation of spectroscopic probes and functional groups for selective chemical modification that facilitates studies of (real-time) protein dynamics and interactions. In this review, we highlight recent methods developed to use UAAs to study chemokine receptors and we describe examples of their use to probe chemokine receptor function. © 2012 Elsevier Ltd. All rights reserved

Autoantibodies targeting G protein-coupled receptors: an evolving history in autoimmunity. Report of the 4th international symposium

G protein-coupled receptors (GPCR) are involved in various physiological and pathophysiological processes. Functional autoantibodies targeting GPCRs have been associated with multiple disease manifestations in this context. Here we summarize and discuss the relevant findings and concepts presented in the biennial International Meeting on autoantibodies targeting GPCRs (the 4th Symposium), held in Lübeck, Germany, 15-16 September 2022. The symposium focused on the current knowledge of these autoantibodies' role in various diseases, such as cardiovascular, renal, infectious (COVID-19), and autoimmune diseases (e.g., systemic sclerosis and systemic lupus erythematosus). Beyond their association with disease phenotypes, intense research related to the mechanistic action of these autoantibodies on immune regulation and pathogenesis has been developed, underscoring the role of autoantibodies targeting GPCRs on disease outcomes and etiopathogenesis. The observation repeatedly highlighted that autoantibodies targeting GPCRs could also be present in healthy individuals, suggesting that anti-GPCR autoantibodies play a physiologic role in modeling the course of diseases. Since numerous therapies targeting GPCRs have been developed, including small molecules and monoclonal antibodies designed for treating cancer, infections, metabolic disorders, or inflammatory conditions, anti-GPCR autoantibodies themselves can serve as therapeutic targets to reduce patients' morbidity and mortality, representing a new area for the development of novel therapeutic interventions