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- EMDB-68262: C5a bound C5aR2 in complex with beta-arrestin1 -

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Basic information

Entry
Database: EMDB / ID: EMD-68262
TitleC5a bound C5aR2 in complex with beta-arrestin1
Map data
Sample
  • Complex: C5a anaphylatoxin chemotactic receptor 2
    • Protein or peptide: C5a anaphylatoxin
    • Protein or peptide: C5a anaphylatoxin chemotactic receptor 2
    • Protein or peptide: Fab30 heavy chain
    • Protein or peptide: Fab30 light chain
    • Protein or peptide: Beta-arrestin-1
KeywordsC5aR2 / GPCR / membrane protein / active / arrestin / C5a / MEMBRANE PROTEIN/IMMUNESYSTEM / 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)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.84 Å
AuthorsQin J / Cai C / Shan M / Zhang Y
Funding support1 items
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, 2026-
Header (metadata) releaseJul 22, 2026-
Map releaseJul 22, 2026-
UpdateJul 22, 2026-
Current statusJul 22, 2026Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_68262.png

Downloads & links

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Map

FileReleased
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.93 Å/pix.
x 320 pix.
= 297.6 Å		0.93 Å/pix.
x 320 pix.
= 297.6 Å		0.93 Å/pix.
x 320 pix.
= 297.6 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.93 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.15
Minimum - Maximum-0.30717126 - 1.1887171
Average (Standard dev.)0.0023893309 (±0.015974391)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 297.6 Å
α=β=γ: 90.0 °

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Supplemental data

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Sample components

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Entire : C5a anaphylatoxin chemotactic receptor 2

EntireName: C5a anaphylatoxin chemotactic receptor 2
Components
  • Complex: C5a anaphylatoxin chemotactic receptor 2
    • Protein or peptide: C5a anaphylatoxin
    • Protein or peptide: C5a anaphylatoxin chemotactic receptor 2
    • Protein or peptide: Fab30 heavy chain
    • Protein or peptide: Fab30 light chain
    • Protein or peptide: Beta-arrestin-1

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Supramolecule #1: C5a anaphylatoxin chemotactic receptor 2

SupramoleculeName: C5a anaphylatoxin chemotactic receptor 2 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: C5a anaphylatoxin

MacromoleculeName: C5a anaphylatoxin / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 8.342727 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
TLQKKIEEIA AKYKHSVVKK CCYDGARVNN DETCEQRAAR ISLGPRCIKA FTECCVVASQ LRANISHKDM QLGR

UniProtKB: Complement C5

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Macromolecule #2: C5a anaphylatoxin chemotactic receptor 2

MacromoleculeName: C5a anaphylatoxin chemotactic receptor 2 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 36.513188 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MGNDSVSYEY GDYSDLSDRP VDCLDGACLA IDPLRVAPLP LYAAIFLVGV PGNAMVAWVA GKVARRRVGA TWLLHLAVAD LLCCLSLPI LAVPIARGGH WPYGAVGCRA LPSIILLTMY ASVLLLAALS ADLCFLALGP AWWSTVQRAC GVQVACGAAW T LALLLTVP ...String:
MGNDSVSYEY GDYSDLSDRP VDCLDGACLA IDPLRVAPLP LYAAIFLVGV PGNAMVAWVA GKVARRRVGA TWLLHLAVAD LLCCLSLPI LAVPIARGGH WPYGAVGCRA LPSIILLTMY ASVLLLAALS ADLCFLALGP AWWSTVQRAC GVQVACGAAW T LALLLTVP SAIYRRLHQE HFPARLQCVV DYGGSSSTEN AVTAIRFLFG FLGPLVAVAS CHSALLCWAA RRCRPLGTAI VV GFFVCWA PYHLLGLVLT VAAPNSALLA RALRAEPLIV GLALAHSCLN PMLFLYFGRA QLRRSLPAAC HWALRESQGQ DE (SEP)VD(SEP)KK(SEP) (TPO)(SEP)HDLVSEME V

UniProtKB: C5a anaphylatoxin chemotactic receptor 2

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Macromolecule #3: Fab30 heavy chain

MacromoleculeName: Fab30 heavy chain / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 24.40718 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: EISEVQLVES GGGLVQPGGS LRLSCAASGF NVYSSSIHWV RQAPGKGLEW VASISSYYGY TYYADSVKGR FTISADTSKN TAYLQMNSL RAEDTAVYYC ARSRQFWYSG LDYWGQGTLV TVSSASTKGP SVFPLAPSSK STSGGTAALG CLVKDYFPEP V TVSWNSGA ...String:
EISEVQLVES GGGLVQPGGS LRLSCAASGF NVYSSSIHWV RQAPGKGLEW VASISSYYGY TYYADSVKGR FTISADTSKN TAYLQMNSL RAEDTAVYYC ARSRQFWYSG LDYWGQGTLV TVSSASTKGP SVFPLAPSSK STSGGTAALG CLVKDYFPEP V TVSWNSGA LTSGVHTFPA VLQSSGLYSL SSVVTVPSSS LGTQTYICNV NHKPSNTKVD KKVEPKSCDK T

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Macromolecule #4: Fab30 light chain

MacromoleculeName: Fab30 light chain / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 23.435064 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: SDIQMTQSPS SLSASVGDRV TITCRASQSV SSAVAWYQQK PGKAPKLLIY SASSLYSGVP SRFSGSRSGT DFTLTISSLQ PEDFATYYC QQYKYVPVTF GQGTKVEIKR TVAAPSVFIF PPSDSQLKSG TASVVCLLNN FYPREAKVQW KVDNALQSGN S QESVTEQD ...String:
SDIQMTQSPS SLSASVGDRV TITCRASQSV SSAVAWYQQK PGKAPKLLIY SASSLYSGVP SRFSGSRSGT DFTLTISSLQ PEDFATYYC QQYKYVPVTF GQGTKVEIKR TVAAPSVFIF PPSDSQLKSG TASVVCLLNN FYPREAKVQW KVDNALQSGN S QESVTEQD SKDSTYSLSS TLTLSKADYE KHKVYACEVT HQGLSSPVTK SFNRGEC

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Macromolecule #5: Beta-arrestin-1

MacromoleculeName: Beta-arrestin-1 / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Bos taurus (domestic cattle)
Molecular weightTheoretical: 38.980805 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: TRVFKKASPN GKLTVYLGKR DFVDHIDLVE PVDGVVLVDP EYLKERRVYV TLTCAFRYGR EDLDVLGLTF RKDLFVANVQ SFPPAPEDK KPLTRLQERL IKKLGEHAYP FTFEIPPNLP CSVTLQPGPE DTGKACGVDY EVKAFCAENL EEKIHKRNSV R LVIEKVQY ...String:
TRVFKKASPN GKLTVYLGKR DFVDHIDLVE PVDGVVLVDP EYLKERRVYV TLTCAFRYGR EDLDVLGLTF RKDLFVANVQ SFPPAPEDK KPLTRLQERL IKKLGEHAYP FTFEIPPNLP CSVTLQPGPE DTGKACGVDY EVKAFCAENL EEKIHKRNSV R LVIEKVQY APERPGPQPT AETTRQFLMS DKPLHLEASL DKEIYYHGEP ISVNVHVTNN TNKTVKKIKI SVRQYADICL FN TAQYKCP VAMEEADDTV APSSTFCKVY TLTPFLANNR EKRGLALDGK LKHEDTNLAS STLLREGANR EILGIIVSYK VKV KLVVSR GGLLGDLASS DVAVELPFTL M

UniProtKB: Beta-arrestin-1

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 52.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 1.5 µm / Nominal defocus min: 0.7000000000000001 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.84 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 111355
Initial angle assignmentType: RANDOM ASSIGNMENT
Final angle assignmentType: MAXIMUM LIKELIHOOD

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