Structural insights into small-molecule agonist recognition and activation of complement receptor C3aR.

ABSTRACT: The complement system plays crucial roles in innate immunity and inflammatory responses. The anaphylatoxin C3a mediates pro-inflammatory and chemotactic functions through the G protein-coupled receptor C3aR. While the active structure of the C3a-C3aR-G_i complex has been determined, the inactive conformation and activation mechanism of C3aR remain elusive. Here we report the cryo-EM structure of ligand-free, G protein-free C3aR, providing insights into its inactive conformation. In addition, we determine the structures of C3aR in complex with the synthetic small-molecule agonist JR14a in two distinct conformational states: a G protein-free intermediate, and a fully active G_i-bound state. The structure of the active JR14a-bound C3aR reveals that JR14a engages in highly

SUBMITTER: Kim J 

PROVIDER: S-EPMC12084609 | biostudies-literature | 2025 May

REPOSITORIES: biostudies-literature