22GK

C5a bound C5aR2 in complex with beta-arrestin1

Summary for 22GK

• Entry DOI: 10.2210/pdb22gk/pdb
• EMDB information: 68262
• Descriptor: C5a anaphylatoxin, C5a anaphylatoxin chemotactic receptor 2, Fab30 heavy chain, ... (5 entities in total)
• Functional Keywords: c5ar2, gpcr, membrane protein, active, arrestin, c5a, membrane protein/immunesystem, membrane protein-immunesystem complex
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 131678.96

Authors

Qin, J.,Cai, C.,Shan, M.,Zhang, Y. (deposition date: 2026-01-09, release date: 2026-07-22)

Primary citation

Qin, J.,Cai, C.,Shan, M.,Zhou, S.,Shen, Q.,Zhu, T.,Zhao, M.,Mei, Y.,Ji, F.,Shen, D.D.,Zang, S.K.,Zhang, H.,Xu, H.,Yang, M.,Wang, W.W.,Xiao, R.,Yang, B.,Mao, C.,Shao, Z.,Wu, H.,Lu, Q.,Zhang, Y.
Atypical signaling, ligand recognition and selective agonist discovery of complement receptor C5aR2.
Cell Res., 2026

PubMed Abstract: C5a, the most potent anaphylatoxin in the complement system, exerts its effects through the canonical G protein-coupled receptor C5aR1 and the arrestin-coupled receptor C5aR2. Despite the critical role of C5aR2 in immunomodulation, the molecular mechanisms underlying its biased signaling, ligand recognition, and associated pathophysiology remain poorly understood. Here, we report cryo-electron microscopy structures of β-arrestin 1-bound C5aR2 and C5aR1 stimulated by C5a or its metabolite C5a. By combining structural analysis with functional assays, we identified the key structural determinants that prevent G protein coupling and confer intrinsic bias toward β-arrestins. Comparative analysis elucidated the distinct ligand recognition mechanism of C5aR2 and explained the retained affinity of C5a for C5aR2. These findings guided the rational design of ZQ105, a highly selective C5aR2 agonist. Leveraging ZQ105 as a chemical probe, functional studies revealed that selective C5aR2 activation induces distinct pro-inflammatory responses and receptor internalization in neutrophils. This study provides novel structural insights into transducer engagement and ligand recognition by C5aR2, yielding a valuable pharmacological tool for exploring C5aR2-related pathophysiological processes.

PubMed: 42399467
DOI: 10.1038/s41422-026-01273-1

Experimental method

ELECTRON MICROSCOPY (2.84 Å)