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- EMDB-62636: Structure of beta-arrestin2 in complex with mouse C5aR1pp -

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Basic information

Entry
Database: EMDB / ID: EMD-62636
TitleStructure of beta-arrestin2 in complex with mouse C5aR1pp
Map data
Sample
  • Complex: beta-arrestin2 in complex with mouse C5aR1pp
    • Complex: Beta-arrestin-2
      • Protein or peptide: Beta-arrestin-2
    • Complex: Fab30 Heavy Chain and Light chain
      • Protein or peptide: Fab30 Heavy Chain
      • Protein or peptide: Fab30 Light Chain
    • Complex: mouse C5aR1 phosphopeptide
      • Protein or peptide: C5a anaphylatoxin chemotactic receptor 1
KeywordsGPCR / G protein / SIGNALING PROTEIN / beta-arrestin
Function / homology
Function and homology information


presynapse organization / Peptide ligand-binding receptors / complement component C5a receptor activity / Regulation of Complement cascade / response to peptidoglycan / angiotensin receptor binding / desensitization of G protein-coupled receptor signaling pathway / G alpha (i) signalling events / G protein-coupled receptor internalization / inositol hexakisphosphate binding ...presynapse organization / Peptide ligand-binding receptors / complement component C5a receptor activity / Regulation of Complement cascade / response to peptidoglycan / angiotensin receptor binding / desensitization of G protein-coupled receptor signaling pathway / G alpha (i) signalling events / G protein-coupled receptor internalization / inositol hexakisphosphate binding / positive regulation of neutrophil chemotaxis / positive regulation of macrophage chemotaxis / phosphatidylinositol-3,4,5-trisphosphate binding / amyloid-beta clearance / positive regulation of vascular endothelial growth factor production / positive regulation of receptor internalization / endocytic vesicle / clathrin-coated pit / neutrophil chemotaxis / Neutrophil degranulation / astrocyte activation / phosphatidylinositol binding / positive regulation of epithelial cell proliferation / mRNA transcription by RNA polymerase II / microglial cell activation / G protein-coupled receptor activity / receptor internalization / cognition / positive regulation of angiogenesis / apical part of cell / protein transport / cytoplasmic vesicle / basolateral plasma membrane / positive regulation of ERK1 and ERK2 cascade / defense response to Gram-positive bacterium / G protein-coupled receptor signaling pathway / signal transduction / nucleus / plasma membrane / cytoplasm
Similarity search - Function
Anaphylatoxin chemotactic receptor, C3a/C5a1/C5a2 / Arrestin, conserved site / Arrestins signature. / Arrestin / Arrestin, N-terminal / Formyl peptide receptor-related / Arrestin-like, N-terminal / Arrestin C-terminal-like domain / Arrestin (or S-antigen), N-terminal domain / Arrestin (or S-antigen), C-terminal domain ...Anaphylatoxin chemotactic receptor, C3a/C5a1/C5a2 / Arrestin, conserved site / Arrestins signature. / Arrestin / Arrestin, N-terminal / Formyl peptide receptor-related / 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 / Arrestin-like, C-terminal / G-protein coupled receptors family 1 signature. / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. / 7 transmembrane receptor (rhodopsin family) / Immunoglobulin E-set
Similarity search - Domain/homology
C5a anaphylatoxin chemotactic receptor 1 / Beta-arrestin-2
Similarity search - Component
Biological speciesBos taurus (domestic cattle) / Mus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.78 Å
AuthorsBanerjee R / Yadav R / Yadav MK / Ganguly M / Mishra S / Dalal A / Gati C / Shukla AK
Funding support India, United Kingdom, 3 items
OrganizationGrant numberCountry
Science and Engineering Research Board (SERB)IPA/2020/000405 India
Wellcome TrustIA/S/20/1/504916 United Kingdom
Science and Engineering Research Board (SERB)CRG/2022/002646 India
CitationJournal: bioRxiv / Year: 2025
Title: Molecular fingerprints of a convergent mechanism orchestrating diverse ligand recognition and species-specific pharmacology at the complement anaphylatoxin receptors.
Authors: Sudha Mishra / Manish K Yadav / Annu Dalal / Manisankar Ganguly / Ravi Yadav / Kazuhiro Sawada / Divyanshu Tiwari / Nabarun Roy / Nilanjana Banerjee / Jenny N Fung / Jianina Marallag / ...Authors: Sudha Mishra / Manish K Yadav / Annu Dalal / Manisankar Ganguly / Ravi Yadav / Kazuhiro Sawada / Divyanshu Tiwari / Nabarun Roy / Nilanjana Banerjee / Jenny N Fung / Jianina Marallag / Cedric S Cui / Xaria X Li / John D Lee / Calvin Aaron Dsouza / Shirsha Saha / Parishmita Sarma / Ganita Rawat / Houming Zhu / Htet A Khant / Richard J Clark / Fumiya K Sano / Ramanuj Banerjee / Trent M Woodruff / Osamu Nureki / Cornelius Gati / Arun K Shukla /
Abstract: Complement anaphylatoxin receptors (C3aR and C5aR1) are prototypical G protein-coupled receptors (GPCRs) playing crucial physiological roles in innate immunity by combating pathogenic infections and ...Complement anaphylatoxin receptors (C3aR and C5aR1) are prototypical G protein-coupled receptors (GPCRs) playing crucial physiological roles in innate immunity by combating pathogenic infections and orchestrating inflammatory responses. They continue to be important therapeutic targets for multiple disorders including autoimmune diseases, acute and chronic inflammation, and allergy-related conditions. Recent structural coverage has provided important insights into their activation and signaling, however, confounding observations in the literature related to ligand efficacy and functional responses, especially in different model systems, present a major challenge for drug discovery efforts. Here, we systematically and comprehensively profile a broad set of natural and synthetic ligands at C3aR and C5aR1 and discover a previously unanticipated level of functional specialization in terms of species-specific pharmacology and receptor activation. Taking a lead from this, we determine seventeen cryo-EM structures of different ligand-receptor-G-protein complexes and uncover distinct orientation of agonists between the human and mouse receptors despite an overlapping positioning in the orthosteric binding pocket. Combined with extensive mutagenesis and functional assays, these structural snapshots allow us to decode and validate a convergent molecular mechanism involving a "Five-Point-Switch" in these receptors that orchestrates the recognition and efficacy of diverse agonists. We also identify species-specific differences at the level of phosphorylation patterns encoded in the carboxyl-terminus of these receptors and directly visualize their impact on βarr binding and activation using cryo-EM structures. Interestingly, we observe that βarrs engage with the mouse C5aR1 using a variation of previously discovered P-X-P-P phosphorylation motif via a "Sliding-Mechanism" and also exhibit distinct oligomeric state for the human vs. mouse receptors. Taken together, this study elucidates functional specialization at the complement anaphylatoxin receptors and underlying molecular mechanisms, offering a previously lacking framework with direct and immediate implications for the development of novel therapeutics.
History
DepositionDec 7, 2024-
Header (metadata) releaseNov 26, 2025-
Map releaseNov 26, 2025-
UpdateNov 26, 2025-
Current statusNov 26, 2025Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_62636.png

Downloads & links

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Map

FileDownload / File: emd_62636.map.gz / Format: CCP4 / Size: 216 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
1.01 Å/pix.
x 384 pix.
= 388.186 Å		1.01 Å/pix.
x 384 pix.
= 388.186 Å		1.01 Å/pix.
x 384 pix.
= 388.186 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.0109 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.165
Minimum - Maximum-0.0009341789 - 2.5052907
Average (Standard dev.)0.0009946252 (±0.026198063)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions384384384
Spacing384384384
CellA=B=C: 388.1856 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_62636_half_map_1.map
Projections & Slices
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Density Histograms

Histogram

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Half map: #1

Fileemd_62636_half_map_2.map
Projections & Slices
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Histogram (log scale)

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Sample components

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Entire : beta-arrestin2 in complex with mouse C5aR1pp

EntireName: beta-arrestin2 in complex with mouse C5aR1pp
Components
  • Complex: beta-arrestin2 in complex with mouse C5aR1pp
    • Complex: Beta-arrestin-2
      • Protein or peptide: Beta-arrestin-2
    • Complex: Fab30 Heavy Chain and Light chain
      • Protein or peptide: Fab30 Heavy Chain
      • Protein or peptide: Fab30 Light Chain
    • Complex: mouse C5aR1 phosphopeptide
      • Protein or peptide: C5a anaphylatoxin chemotactic receptor 1

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Supramolecule #1: beta-arrestin2 in complex with mouse C5aR1pp

SupramoleculeName: beta-arrestin2 in complex with mouse C5aR1pp / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all

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Supramolecule #2: Beta-arrestin-2

SupramoleculeName: Beta-arrestin-2 / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1
Source (natural)Organism: Bos taurus (domestic cattle)

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Supramolecule #3: Fab30 Heavy Chain and Light chain

SupramoleculeName: Fab30 Heavy Chain and Light chain / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #2-#3
Source (natural)Organism: Mus musculus (house mouse)

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Supramolecule #4: mouse C5aR1 phosphopeptide

SupramoleculeName: mouse C5aR1 phosphopeptide / type: complex / ID: 4 / Parent: 1 / Macromolecule list: #4

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Macromolecule #1: Beta-arrestin-2

MacromoleculeName: Beta-arrestin-2 / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Bos taurus (domestic cattle)
Molecular weightTheoretical: 47.217676 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MGEKPGTRVF KKSSPNGKLT VYLGKRDFVD HLDKVDPVDG VVLVDPDYLK DRKVFVTLTV AFRYGREDCD VLGLSFRKDL FIANYQAFP PTPNPPRPPT RLQERLLRKL GQHAHPFFFT IPQNLPSSVT LQPGPEDTGK ALGVDFEIRA FVAKSLEEKS H KRNSVRLV ...String:
MGEKPGTRVF KKSSPNGKLT VYLGKRDFVD HLDKVDPVDG VVLVDPDYLK DRKVFVTLTV AFRYGREDCD VLGLSFRKDL FIANYQAFP PTPNPPRPPT RLQERLLRKL GQHAHPFFFT IPQNLPSSVT LQPGPEDTGK ALGVDFEIRA FVAKSLEEKS H KRNSVRLV IRKVQFAPEK PGPQPSAETT RHFLMSDRSL HLEASLDKEL YYHGEPLNVN VHVTNNSTKT VKKIKVSVRQ YA DIVLFST AQYKVPVAQV EQDDQVSPSS TFSKVYTITP FLANNREKRG LALDGKLKHE DTNLASSTIV KEGANKEVLG ILV SYRVKV KLVVSRGGDV SVELPFVLMH PKPHDHIALP RPQSAATHPP TLLPSAVPET DAPVDTNLIE FETNYATDDD IVFE DFARL RLKGLKDEDY DDQFC

UniProtKB: Beta-arrestin-2

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Macromolecule #2: Fab30 Heavy Chain

MacromoleculeName: Fab30 Heavy Chain / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 25.512354 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 THHHHHHHH

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Macromolecule #3: Fab30 Light Chain

MacromoleculeName: Fab30 Light Chain / type: protein_or_peptide / ID: 3 / Number of copies: 2 / 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 #4: C5a anaphylatoxin chemotactic receptor 1

MacromoleculeName: C5a anaphylatoxin chemotactic receptor 1 / type: protein_or_peptide / ID: 4 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 2.892318 KDa
SequenceString:
GGGDSK(TPO)F(TPO)P (SEP)(TPO)(TPO)D(TPO)(SEP)TRKS QAV

UniProtKB: C5a anaphylatoxin chemotactic receptor 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: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Detector mode: COUNTING / Average electron dose: 53.7 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 3.0 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionSoftware - Name: cryoSPARC (ver. 4.6.2) / Type: NONE
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

8j8v

Final reconstructionApplied symmetry - Point group: C2 (2 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 2.78 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4.6.2) / Number images used: 285699
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.6.2)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.6.2)
Final 3D classificationSoftware - Name: cryoSPARC (ver. 4.6.2)
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: FLEXIBLE FIT
Output model

PDB-9ky2:
Structure of beta-arrestin2 in complex with mouse C5aR1pp

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