Interaction of Phosphorylated <scp>C5aR1</scp> With β‐Arrestin1: A Comparative Structural Modeling Study

The complement system is an essential element of the immune response, significantly contributing to the body's defense against pathogens by augmenting inflammation, opsonizing pathogens, and promoting cell lysis. The C5aR1 and C5aR2, which interact with the highly potent complement fragment C5a, are a crucial part of this system. C5aR1, a classical G protein-coupled receptor (GPCR), activates G-proteins upon binding C5a and triggers the proinflammatory signaling cascades. However, C5aR1, upon phosphorylation, also interacts with β-arrestins, which desensitize G-protein signaling and activate alternative signaling pathways, thereby influencing immune responses and triggering receptor internalization. Thus, structurally establishing the interaction between the binary complex of C5a-C5aR1 and β-arrestins is essential for effectively targeting C5aR1 signaling pathways. Notably, we have earlier elaborated the model ternary complex of unphosphorylated C5aR2 with β-arrestin1. In the absence of structural data related to the fully active ternary complex of C5a-C5aR1-β-arrestin1, the current study hypothesizes two plausible models ("front-end" and "back-end"), focusing on the cytosolic side interaction of the fully phosphorylated C-terminus peptide stretch of C5aR1 with the β-arrestin1, as the interaction of this section is not resolved in any reported ternary complexes of other GPCRs, including C5aR1. The two model complexes have been subjected to 1 μs of molecular dynamics (MD) simulations each and further compared energetically for their physical sustainability. The proposed ternary model complexes of C5a-C5aR1-β-arrestin1 fill the gulf and enhance the existing structural knowledge regarding the interactions of β-arrestins with C5aR1, which may open new avenues for targeting G-protein or β-arrestin-biased signaling.