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- PDB-22gk: C5a bound C5aR2 in complex with beta-arrestin1 -

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Basic information

Entry
Database: PDB / ID: 22gk
TitleC5a bound C5aR2 in complex with beta-arrestin1
Components
  • Beta-arrestin-1
  • C5a anaphylatoxin
  • C5a anaphylatoxin chemotactic receptor 2
  • Fab30 heavy chain
  • Fab30 light chain
KeywordsMEMBRANE PROTEIN/IMMUNESYSTEM / C5aR2 / GPCR / membrane protein / active / arrestin / C5a / MEMBRANE PROTEIN-IMMUNESYSTEM complex
Function / homology
Function and homology information


TGFBR3 regulates TGF-beta signaling / MAP2K and MAPK activation / Activation of SMO / Golgi Associated Vesicle Biogenesis / regulation of interleukin-8 production / Lysosome Vesicle Biogenesis / Terminal pathway of complement / membrane attack complex / complement component C5a receptor activity / AP-2 adaptor complex binding ...TGFBR3 regulates TGF-beta signaling / MAP2K and MAPK activation / Activation of SMO / Golgi Associated Vesicle Biogenesis / regulation of interleukin-8 production / Lysosome Vesicle Biogenesis / Terminal pathway of complement / membrane attack complex / complement component C5a receptor activity / AP-2 adaptor complex binding / Ub-specific processing proteases / clathrin coat of coated pit / Cargo recognition for clathrin-mediated endocytosis / clathrin heavy chain binding / negative regulation of neutrophil chemotaxis / Activation of C3 and C5 / Clathrin-mediated endocytosis / negative regulation of macrophage chemotaxis / complement activation, GZMK pathway / other organism cell membrane / clathrin-dependent endocytosis / desensitization of G protein-coupled receptor signaling pathway / acetylcholine receptor binding / complement receptor mediated signaling pathway / complement activation, alternative pathway / G protein-coupled receptor internalization / inositol hexakisphosphate binding / chemokine activity / Thrombin signalling through proteinase activated receptors (PARs) / G alpha (s) signalling events / clathrin binding / sensory perception / negative regulation of interleukin-6 production / endopeptidase inhibitor activity / small molecule binding / pseudopodium / phosphatidylinositol-3,4,5-trisphosphate binding / negative regulation of Notch signaling pathway / positive regulation of receptor internalization / negative regulation of tumor necrosis factor production / complement activation, classical pathway / positive regulation of vascular endothelial growth factor production / positive regulation of chemokine production / Regulation of Complement cascade / basal plasma membrane / Peptide ligand-binding receptors / receptor internalization / positive regulation of protein phosphorylation / G protein-coupled receptor binding / chemotaxis / G protein-coupled receptor activity / apical part of cell / phospholipase C-activating G protein-coupled receptor signaling pathway / protein transport / positive regulation of cytosolic calcium ion concentration / cytoplasmic vesicle / killing of cells of another organism / G alpha (i) signalling events / molecular adaptor activity / basolateral plasma membrane / ubiquitin-dependent protein catabolic process / positive regulation of ERK1 and ERK2 cascade / cell surface receptor signaling pathway / inflammatory response / G protein-coupled receptor signaling pathway / signaling receptor binding / signal transduction / DNA-templated transcription / : / extracellular exosome / extracellular region / nucleus / plasma membrane / cytosol / cytoplasm
Similarity search - Function
: / Complement component 5, CUB domain / Anaphylatoxin chemotactic receptor, C3a/C5a1/C5a2 / Arrestin, conserved site / Arrestins signature. / Arrestin / Arrestin, N-terminal / Formyl peptide receptor-related / Complement C3/4/5, macroglobulin domain MG1 / Macroglobulin domain MG1 ...: / Complement component 5, CUB domain / Anaphylatoxin chemotactic receptor, C3a/C5a1/C5a2 / Arrestin, conserved site / Arrestins signature. / Arrestin / Arrestin, N-terminal / Formyl peptide receptor-related / Complement C3/4/5, macroglobulin domain MG1 / Macroglobulin domain MG1 / Arrestin-like, N-terminal / Arrestin C-terminal-like domain / Arrestin (or S-antigen), N-terminal domain / Arrestin (or S-antigen), C-terminal domain / Arrestin (or S-antigen), C-terminal domain / Anaphylatoxin, complement system domain / Anaphylatoxin domain signature. / Anaphylatoxin, complement system / Anaphylatoxin/fibulin / Anaphylotoxin-like domain / Anaphylatoxin domain profile. / Anaphylatoxin homologous domain / Arrestin-like, C-terminal / Netrin C-terminal Domain / Netrin module, non-TIMP type / UNC-6/NTR/C345C module / Macroglobulin domain MG4 / Macroglobulin domain MG4 / Alpha-macroglobulin, receptor-binding / Alpha-macroglobulin, receptor-binding domain superfamily / Macroglobulin domain MG3 / : / A-macroglobulin receptor binding domain / Macroglobulin domain MG3 / A-macroglobulin receptor / Netrin domain / NTR domain profile. / Alpha-2-macroglobulin / Macroglobulin domain / Alpha-2-macroglobulin, bait region domain / Alpha-macroglobulin-like, TED domain / Alpha-2-macroglobulin family / MG2 domain / A-macroglobulin TED domain / Alpha-2-macroglobulin bait region domain / Alpha-2-Macroglobulin / Alpha-2-macroglobulin family / Tissue inhibitor of metalloproteinases-like, OB-fold / Terpenoid cyclases/protein prenyltransferase alpha-alpha toroid / Immunoglobulin E-set / 7 transmembrane receptor (rhodopsin family) / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. / Immunoglobulin-like fold
Similarity search - Domain/homology
Complement C5 / Beta-arrestin-1 / C5a anaphylatoxin chemotactic receptor 2
Similarity search - Component
Biological speciesHomo sapiens (human)
Mus musculus (house mouse)
Bos taurus (domestic cattle)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.84 Å
AuthorsQin, J. / Cai, C. / Shan, M. / Zhang, Y.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Cell Res / Year: 2026
Title: Atypical signaling, ligand recognition and selective agonist discovery of complement receptor C5aR2.
Authors: Jiao 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 / ...Authors: Jiao 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 /
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 ...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.
History
DepositionJan 9, 2026Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Jul 22, 2026Provider: repository / Type: Initial release
Revision 1.0Jul 22, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Jul 22, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Jul 22, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
C: C5a anaphylatoxin
R: C5a anaphylatoxin chemotactic receptor 2
H: Fab30 heavy chain
L: Fab30 light chain
A: Beta-arrestin-1


Theoretical massNumber of molelcules
Total (without water)131,6795
Polymers131,6795
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein C5a anaphylatoxin


Mass: 8342.727 Da / Num. of mol.: 1 / Mutation: C27R
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: C5, CPAMD4 / Production host: Escherichia coli (E. coli) / References: UniProt: P01031
#2: Protein C5a anaphylatoxin chemotactic receptor 2 / Complement component 5a receptor 2 / G-protein coupled receptor 77


Mass: 36513.188 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: C5AR2, C5L2, GPR77 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q9P296
#3: Antibody Fab30 heavy chain


Mass: 24407.180 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Escherichia coli (E. coli)
#4: Antibody Fab30 light chain


Mass: 23435.064 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Escherichia coli (E. coli)
#5: Protein Beta-arrestin-1 / Arrestin beta-1 / Arrestin-2


Mass: 38980.805 Da / Num. of mol.: 1 / Mutation: R169E
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Bos taurus (domestic cattle) / Gene: ARRB1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P17870
Has ligand of interestN
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: C5a anaphylatoxin chemotactic receptor 2 / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
21Homo sapiens (human)9606
31Bos taurus (domestic cattle)9913
41Mus musculus (house mouse)10090
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
21Spodoptera frugiperda (fall armyworm)7108
31Escherichia coli (E. coli)562
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1500 nm / Nominal defocus min: 700 nm / Cs: 2.7 mm
Image recordingElectron dose: 52 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

EM software
IDNameVersionCategory
1RELION4particle selection
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.84 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 111355 / Symmetry type: POINT

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