Molecular basis of complement anaphylatoxin receptor activation, regulation, selectivity and signaling bias - Abstract – Molecular basis of complement anaphylatoxin receptor activation, regulation, selectivity and signaling bias The complement system is a vital part of the immune system, involved in promoting inflammation and clearance of pathogens. Dysregulation of this system has been linked to various diseases, including autoimmune disorders, neurodegenerative conditions, and cancer. Understanding the molecular mechanisms underlying complement activation and signaling is crucial for therapeutic development. This study aims to investigate the molecular basis of complement anaphylatoxin receptor activation, regulation, selectivity, and signaling bias. As part of our studies, we will obtain valuable insights through structural determination and characterization of these receptors, revealing unique binding pocket topologies and details of receptor activation, and signaling. The specific aims of the study are: 1) elucidating the mechanisms of receptor activation and beta-arrestin recruitment, 2) identifying molecular determinants of signaling bias and receptor selectivity, and 3) investigating immune response regulation and antagonism of complement receptors. The research strategy involves cryo-electron microscopy, signaling assays, and structural and biochemical techniques. The significance of this work lies in its potential to advance our understanding of complement receptor biology, provide frameworks for drug design, and offer new insights into immunomodulatory roles of these receptors. The findings could lead to the development of novel compounds and contribute to the understanding of complement receptor functions in physiology and disease contexts. This study represents one of the most comprehensive investigations of any GPCR subfamily to date and aims to address long-standing questions regarding ligand selectivity, signaling bias, regulation, and antagonism. The results will have implications for the development of tool compounds and therapeutic interventions targeting complement receptors and have the potential to impact a wide range of diseases associated with complement system dysfunction.
