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Atypical signaling, ligand recognition and selective agonist discovery of complement receptor C5aR2

Jiao Qin^1,† , Chenxi Cai^1,† , Mayu Shan^1,† , Suqing Zhou^2,† , Qingya Shen^1,† , Tianyi Zhu³ , Mingming Zhao² , Yang Mei² , Fanghan Ji² , Dan-Dan Shen¹ , Shao-Kun Zang¹ , Huibing Zhang¹ , Haomang Xu¹ , Ming Yang² , Wei-Wei Wang^1,4 , Rong Xiao² , Bing Yang³ , Chunyou Mao⁵ , Zhenhua Shao^6,7,* , Haijing Wu^2,8,* , Qianjin Lu^9,10,11,* , Yan Zhang^1,*

¹Department of Pathology of Sir Run Run Shaw Hospital, Department of Pharmacology, MOE Frontier Science Center for Brain Research and Brain–Machine Integration, and Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
²Department of Dermatology, the Second Xiangya Hospital, Central South University, Hunan Key Laboratory of Medical Epigenomics, Changsha, Hunan, China
³Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, China
⁴Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
⁵Center for Structural Pharmacology and Therapeutics Development, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
⁶Division of Nephrology and Kidney Research Institute, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
⁷Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu, Sichuan, China
⁸The Furong Laboratory, Changsha, Hunan, China
⁹Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, Jiangsu, China
¹⁰Key Laboratory of Basic and Translational Research on Immune-Mediated Skin Diseases, Chinese Academy of Medical Sciences, Nanjing, Jiangsu, China
¹¹Jiangsu Provincial Key Laboratory of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, Jiangsu, China
^†These authors contributed equally: Jiao Qin, Chenxi Cai, Mayu Shan, Suqing Zhou, Qingya Shen
* Correspondence: Zhenhua Shao(zhenhuashao@scu.edu.cn)Haijing Wu(chriswu1010@csu.edu.cn)Qianjin Lu(qianlu5860@pumcderm.cams.cn)Yan Zhang(zhang_yan@zju.edu.cn)

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 C5adesArg. 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 C5adesArg 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.

https://doi.org/10.1038/s41422-026-01273-1

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