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- EMDB-62649: Structure of beta-arrestin1 in complex with mouse C5aR1pp -

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Entry
Database: EMDB / ID: EMD-62649
TitleStructure of beta-arrestin1 in complex with mouse C5aR1pp
Map data
Sample
  • Complex: beta-arrestin1 in complex with mouse C5aR1pp
    • Complex: Beta-arrestin-1
      • Protein or peptide: Beta-arrestin-1
    • 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: C5aR1 phosphopeptide
KeywordsGPCR / G protein / SIGNALING PROTEIN / beta-arrestin
Function / homology
Function and homology information


V2 vasopressin receptor binding / alpha-1A adrenergic receptor binding / follicle-stimulating hormone receptor binding / TGFBR3 regulates TGF-beta signaling / sensory perception of touch / G alpha (s) signalling events / presynapse organization / regulation of inositol trisphosphate biosynthetic process / follicle-stimulating hormone signaling pathway / protein phosphorylated amino acid binding ...V2 vasopressin receptor binding / alpha-1A adrenergic receptor binding / follicle-stimulating hormone receptor binding / TGFBR3 regulates TGF-beta signaling / sensory perception of touch / G alpha (s) signalling events / presynapse organization / regulation of inositol trisphosphate biosynthetic process / follicle-stimulating hormone signaling pathway / protein phosphorylated amino acid binding / alpha-1B adrenergic receptor binding / Peptide ligand-binding receptors / Lysosome Vesicle Biogenesis / complement component C5a receptor activity / Regulation of Complement cascade / AP-2 adaptor complex binding / response to peptidoglycan / Ub-specific processing proteases / angiotensin receptor binding / MAP2K and MAPK activation / Golgi Associated Vesicle Biogenesis / Cargo recognition for clathrin-mediated endocytosis / G alpha (i) signalling events / clathrin adaptor activity / Clathrin-mediated endocytosis / negative regulation of interleukin-8 production / regulation of G protein-coupled receptor signaling pathway / cysteine-type endopeptidase inhibitor activity involved in apoptotic process / arrestin family protein binding / G protein-coupled receptor internalization / mitogen-activated protein kinase kinase binding / positive regulation of neutrophil chemotaxis / Thrombin signalling through proteinase activated receptors (PARs) / response to morphine / clathrin binding / stress fiber assembly / positive regulation of Rho protein signal transduction / positive regulation of macrophage chemotaxis / pseudopodium / amyloid-beta clearance / negative regulation of interleukin-6 production / positive regulation of vascular endothelial growth factor production / positive regulation of receptor internalization / negative regulation of Notch signaling pathway / phototransduction / positive regulation of insulin secretion involved in cellular response to glucose stimulus / insulin-like growth factor receptor binding / clathrin-coated pit / neutrophil chemotaxis / Neutrophil degranulation / negative regulation of protein ubiquitination / astrocyte activation / GTPase activator activity / positive regulation of protein ubiquitination / nuclear estrogen receptor binding / positive regulation of epithelial cell proliferation / phosphoprotein binding / mRNA transcription by RNA polymerase II / microglial cell activation / G protein-coupled receptor binding / G protein-coupled receptor activity / negative regulation of ERK1 and ERK2 cascade / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / cognition / endocytosis / positive regulation of protein phosphorylation / positive regulation of angiogenesis / apical part of cell / protein transport / cytoplasmic vesicle / ubiquitin-dependent protein catabolic process / regulation of apoptotic process / basolateral plasma membrane / dendritic spine / molecular adaptor activity / proteasome-mediated ubiquitin-dependent protein catabolic process / negative regulation of neuron apoptotic process / transmembrane transporter binding / postsynaptic membrane / transcription coactivator activity / positive regulation of ERK1 and ERK2 cascade / endosome / positive regulation of MAPK cascade / defense response to Gram-positive bacterium / postsynaptic density / protein ubiquitination / G protein-coupled receptor signaling pathway / response to xenobiotic stimulus / signaling receptor binding / positive regulation of cell population proliferation / ubiquitin protein ligase binding / regulation of DNA-templated transcription / regulation of transcription by RNA polymerase II / negative regulation of apoptotic process / chromatin / glutamatergic synapse / enzyme binding / positive regulation of transcription by RNA polymerase II / nucleus / plasma membrane
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
Beta-arrestin-1 / C5a anaphylatoxin chemotactic receptor 1
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat) / Mus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.72 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 9, 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_62649.png

Downloads & links

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Map

FileDownload / File: emd_62649.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: 0.0269
Minimum - Maximum-0.039292037 - 1.7869805
Average (Standard dev.)0.00051384047 (±0.013356369)
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_62649_half_map_1.map
Projections & Slices
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Histogram

Histogram (log scale)

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Half map: #1

Fileemd_62649_half_map_2.map
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Sample components

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Entire : beta-arrestin1 in complex with mouse C5aR1pp

EntireName: beta-arrestin1 in complex with mouse C5aR1pp
Components
  • Complex: beta-arrestin1 in complex with mouse C5aR1pp
    • Complex: Beta-arrestin-1
      • Protein or peptide: Beta-arrestin-1
    • 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: C5aR1 phosphopeptide

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Supramolecule #1: beta-arrestin1 in complex with mouse C5aR1pp

SupramoleculeName: beta-arrestin1 in complex with mouse C5aR1pp / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all

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Supramolecule #2: Beta-arrestin-1

SupramoleculeName: Beta-arrestin-1 / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1
Source (natural)Organism: Rattus norvegicus (Norway rat)

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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: #3-#4
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: #2

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Macromolecule #1: Beta-arrestin-1

MacromoleculeName: Beta-arrestin-1 / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Rattus norvegicus (Norway rat)
Molecular weightTheoretical: 47.088508 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MGDKGTRVFK KASPNGKLTV YLGKRDFVDH IDLVDPVDGV VLVDPEYLKE RRVYVTLTCA FRYGREDLDV LGLTFRKDLF VANVQSFPP APEDKKPLTR LQERLIKKLG EHAYPFTFEI PPNLPCSVTL QPGPEDTGKA CGVDYEVKAF CAENLEEKIH K RNSVRLVI ...String:
MGDKGTRVFK KASPNGKLTV YLGKRDFVDH IDLVDPVDGV VLVDPEYLKE RRVYVTLTCA FRYGREDLDV LGLTFRKDLF VANVQSFPP APEDKKPLTR LQERLIKKLG EHAYPFTFEI PPNLPCSVTL QPGPEDTGKA CGVDYEVKAF CAENLEEKIH K RNSVRLVI RKVQYAPERP GPQPTAETTR QFLMSDKPLH LEASLDKEIY YHGEPISVNV HVTNNTNKTV KKIKISVRQY AD ICLFNTA QYKCPVAMEE ADDTVAPSST FCKVYTLTPF LANNREKRGL ALDGKLKHED TNLASSTLLR EGANREILGI IVS YKVKVK LVVSRGGLLG DLASSDVAVE LPFTLMHPKP KEEPPHREVP ESETPVDTNL IELDTNDDDI VFEDFARQRL KGMK DDKDE EDDGTGSPHL NNR

UniProtKB: Beta-arrestin-1

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Macromolecule #2: C5aR1 phosphopeptide

MacromoleculeName: C5aR1 phosphopeptide / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 2.972297 KDa
SequenceString:
GGGD(SEP)K(TPO)F(TPO)P (SEP)(TPO)(TPO)D(TPO)(SEP)TRKS QAV

UniProtKB: C5a anaphylatoxin chemotactic receptor 1

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Macromolecule #3: Fab30 Heavy Chain

MacromoleculeName: Fab30 Heavy Chain / type: protein_or_peptide / ID: 3 / 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 #4: Fab30 Light Chain

MacromoleculeName: Fab30 Light Chain / type: protein_or_peptide / ID: 4 / 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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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:

8j8z

Final reconstructionApplied symmetry - Point group: C2 (2 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 2.72 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4.6.2) / Number images used: 376105
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-9kyu:
Structure of beta-arrestin1 in complex with mouse C5aR1pp

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