Emerging Insights into the Structure and Function of Complement C5a Receptors.

Complement factor C5a is an integral constituent of the complement cascade critically involved in the innate immune response, and it exerts its functions via two distinct receptors, C5aR1 and C5aR2. While C5aR1 is a prototypical G-protein-coupled receptor (GPCR), C5aR2 lacks functional coupling to heterotrimeric G proteins, although both receptors efficiently recruit β arrestins (βarrs). Here, we discuss the recent studies providing direct structural details of ligand–receptor interactions, and a framework of functional bias in this system, including the differences in terms of structural motifs and transducer coupling. We also discuss the functional analogy of C5aR2 with the atypical chemokine receptors (ACKRs), and highlight the future directions to elucidate the mechanistic basis of the functional divergence of these receptors activated by a common natural agonist. The complement cascade is a critical part of our innate immune system that plays a crucial role in combating pathogenic infections. Complement C5a, a potent anaphylatoxin in the complement cascade, activates two different seven transmembrane receptors, namely C5aR1 and C5aR2. C5aR1 is a prototypical GPCR, while C5aR2, which exhibits functional analogy to ACKRs, does not exhibit any functional coupling to G proteins but engages βarrs upon activation. Crystal structures of C5aR1 in complex with antagonists have provided important insights into ligand–receptor interaction and a potential template for novel ligand discovery. Ligand-specific functional bias at C5aR1 has been discovered recently that offers a potential framework for better therapeutic intervention. [ABSTRACT FROM AUTHOR]