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TitleAtypical signaling, ligand recognition and selective agonist discovery of complement receptor C5aR2.
Journal, issue, pagesCell Res., Year 2026
Publish dateJun 2, 2026
AuthorsJiao Qin / Chenxi Cai / Mayu Shan / Suqing Zhou / Qingya Shen / Tianyi Zhu / Mingming Zhao / Yang Mei / Fanghan Ji / Dan-Dan Shen / Shao-Kun Zang / Huibing Zhang / Haomang Xu / Ming Yang / Wei-Wei Wang / Rong Xiao / Bing Yang / Chunyou Mao / Zhenhua Shao / Haijing Wu / Qianjin Lu / Yan Zhang /
PubMed AbstractC5a, 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 ...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.
External linksCell Res. / PubMed:42399467
MethodsEM (single particle)
Resolution2.7 - 3.3 Å
Structure data

68177
EMDB Unreleased entry

EMDB-68177, PDB-22cr:
C5a-desArg bound C5aR2 in complex with beta-arrestin1
Method: EM (single particle) / Resolution: 2.9 Å

68262
EMDB Unreleased entry

EMDB-68262, PDB-22gk:
C5a bound C5aR2 in complex with beta-arrestin1
Method: EM (single particle) / Resolution: 2.84 Å

68263
EMDB Unreleased entry

EMDB-68263, PDB-22gl:
C5a bound C5aR1 in complex with beta-arrestin1
Method: EM (single particle) / Resolution: 3.3 Å

68264
EMDB Unreleased entry

EMDB-68264, PDB-22gm:
C5a bound C5aR1 in complex with beta-arrestin1
Method: EM (single particle) / Resolution: 2.7 Å


EMDB Unreleased entry

EMDB-68516: C5a bound C5aR2 in complex with beta-arrestin1
Method: EM (single particle) / Resolution: 2.84 Å


EMDB Unreleased entry

EMDB-68517: C5a bound C5aR2 in complex with beta-arrestin1(focused on Receptor)
Method: EM (single particle) / Resolution: 3.0 Å


EMDB Unreleased entry

EMDB-68520: C5a bound C5aR1(V2R C tail) in complex with beta-arrestin1 (Focus on Receptor)
Method: EM (single particle) / Resolution: 2.9 Å


EMDB Unreleased entry

EMDB-68524: C5a bound C5aR1(V2R C tail) in complex with beta-arrestin1
Method: EM (single particle) / Resolution: 2.7 Å


EMDB Unreleased entry

EMDB-68525: C5a bound C5aR1(V2R C tail) in complex with beta-arrestin1 (Focus on Arrestin)
Method: EM (single particle) / Resolution: 2.7 Å


EMDB Unreleased entry

EMDB-68529: C5a-desArg bound C5aR2 in complex with beta-arrestin1(focus on receptor)
Method: EM (single particle) / Resolution: 3.1 Å


EMDB Unreleased entry

EMDB-68531: C5a-desArg bound C5aR2 in complex with beta-arrestin1
Method: EM (single particle) / Resolution: 3.0 Å


EMDB Unreleased entry

EMDB-68534: C5a-desArg bound C5aR2 in complex with beta-arrestin1 (Focus on Arrestin)
Method: EM (single particle) / Resolution: 2.9 Å


EMDB Unreleased entry

EMDB-77405: C5a bound C5aR2 in complex with beta-arrestin1 (focused on barr1-Fab30 complex)
Method: EM (single particle) / Resolution: 2.8 Å

Source
  • homo sapiens (human)
  • mus musculus (house mouse)
  • bos taurus (domestic cattle)
KeywordsMEMBRANE PROTEIN/IMMUNE SYSTEM / C5aR2 / GPCR / membrane protein / active / arrestin / C5a-desArg / MEMBRANE PROTEIN-IMMUNE SYSTEM complex / MEMBRANE PROTEIN/IMMUNESYSTEM / C5a / MEMBRANE PROTEIN-IMMUNESYSTEM complex

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