C5aR2 receptor: The genomic twin of the flamboyant C5aR1

Abstract The complement fragment C5a is one of the most potent proinflammatory glycoproteins liberated by the activation of the biochemical cascade of the complement system. C5a is established to interact with a set of genomically related transmembrane receptors, like C5aR1 (CD88, C5aR) and C5aR2 (GPR77, C5L2) with comparable affinity. The C5aR1 is a classical G‐protein‐coupled receptor (GPCR), whereas C5aR2 is a nonclassical GPCR that tailors immune cell activity potentially through β‐arrestins rather than G‐proteins. Currently, the exact function of the C5aR2 is actively debated in the context of C5aR1, even though both C5aR1 and C5aR2 are coexpressed on myriads of tissues. The functional relevance of C5aR2 appears to be context‐dependent compared to the C5aR1, which has received enormous attention for its role in both acute and chronic inflammatory diseases. In addition, the structure of C5aR2 and its interaction specificity toward C5a is not structurally elucidated in the literature so far. The current study has attempted to close the gap by generating highly refined model structures of C5aR2, respectively in free (inactive), complexed to C‐terminal peptide of C5a (meta‐active) and the C5a (active), embedded to a model palmitoyl‐2‐oleoyl‐sn‐glycero‐3‐phosphocholine bilayer. The computational modeling and the 1.5‐μs molecular dynamics data presented in the current study are expected to further enrich the understanding of C5a–C5aR2 interaction compared to C5a–C5aR1, which will surely help in elaborating the currently debated biological function of C5aR2 better in the foreseeable future.