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

Area of Science:

• Structural biology
• Immunology
• Biochemistry

Background:

• The complement system is vital for innate immunity and inflammation.
• The anaphylatoxin C3a receptor (C3aR) mediates inflammatory responses via G protein signaling.
• Understanding C3aR's inactive state and activation mechanism is crucial.

Purpose of the Study:

• To determine the cryo-EM structure of ligand-free C3aR.
• To elucidate the conformational changes and activation mechanism of C3aR.
• To provide a molecular basis for C3aR's high basal activity.

Main Methods:

• Cryo-electron microscopy (cryo-EM) to determine C3aR structures.
• Structural analysis of C3aR in apo, intermediate, and active states.
• Comparison of C3aR-ligand interactions with C3a.

Main Results:

• Determined the cryo-EM structure of inactive, ligand-free C3aR.
• Resolved structures of C3aR with agonist JR14a in intermediate and active states.
• Identified conserved and specific interactions of JR14a with C3aR.
• Revealed insights into C3aR's conformational landscape and activation pathway.

Conclusions:

• The study provides the first structures of inactive and intermediate C3aR conformations.
• Structural insights explain C3aR's high basal activity.
• Findings may guide the development of therapeutics for complement-mediated inflammatory diseases.