9ISI

Structure of human C3aR in apo state

Summary for 9ISI

• Entry DOI: 10.2210/pdb9isi/pdb
• EMDB information: 60836
• Descriptor: C3a anaphylatoxin chemotactic receptor,Soluble cytochrome b562 (1 entity in total)
• Functional Keywords: gpcr, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 1
• Total formula weight: 68608.29

Authors

Kim, J.,Ko, S.,Choi, H.-J. (deposition date: 2024-07-17, release date: 2025-04-23, Last modification date: 2025-07-16)

Primary citation

Kim, J.,Ko, S.,Choi, C.,Bae, J.,Byeon, H.,Seok, C.,Choi, H.J.
Structural insights into small-molecule agonist recognition and activation of complement receptor C3aR.
Embo J., 44:2803-2826, 2025

PubMed 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 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-bound state. The structure of the active JR14a-bound C3aR reveals that JR14a engages in highly conserved interactions with C3aR, similar to the binding of the C-terminal pentapeptide of C3a, along with JR14a-specific interactions. Structural comparison of C3aR in the apo, intermediate, and fully active states provides novel insights into the conformational landscape and activation mechanism of C3aR and defines a molecular basis explaining its high basal activity. Our results may aid in the rational design of therapeutics targeting complement-related inflammatory disorders.

PubMed: 40195498
DOI: 10.1038/s44318-025-00429-w

Experimental method

ELECTRON MICROSCOPY (3.56 Å)