Molecular basis of diverse ligand recognition and species-specific pharmacology at the complement anaphylatoxin receptor C3aR.

The complement anaphylatoxin receptor, C3aR, is a prototypical G protein-coupled receptor (GPCR) that plays multi-faceted roles in immune regulation, pro-inflammatory responses, neuroimmune modulation, and host defense mechanisms against pathogens. Recent structural coverage has provided important insights into C3aR activation and signaling, however, confounding observations in the literature related to ligand efficacy and functional responses present a major challenge for drug discovery efforts. Here, we systematically and comprehensively profile a broad set of natural and synthetic ligands at C3aR, and demonstrate functional specialization in terms of species-specific pharmacology, receptor activation, and signaling-bias. Taking a lead from this, we determine seven cryo-EM structures of C3aR, and employ structure-guided site-directed mutagenesis studies to decode a convergent molecular mechanism that orchestrates the recognition and efficacy of diverse agonists. This study elucidates key molecular insights into C3aR activation and signaling with direct implications for therapeutic design.