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-Gi1 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 Gi1-bound state. The structure of the active JR14a-bound C3aR reveals that JR14a engages in highly conserved interactio

SUBMITTER: Jinuk Kim 

PROVIDER: S-SCDT-10_1038-S44318-025-00429-W | biostudies-other |

REPOSITORIES: biostudies-other