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- EMDB-64761: Structure of C5a anaphylatoxin chemotactic receptor 2, C5aR2 boun... -

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Basic information

Entry
Database: EMDB / ID: EMD-64761
TitleStructure of C5a anaphylatoxin chemotactic receptor 2, C5aR2 bound to C5a-pep
Map data
Sample
  • Complex: C5aR2 bound to C5a-pep
    • Protein or peptide: C5a-pep ligand
    • Protein or peptide: C5a anaphylatoxin chemotactic receptor 2
KeywordsG protein coupled receptor / G protein / Membrane protein / Immunite system / SIGNALING PROTEIN
Function / homology
Function and homology information


regulation of interleukin-8 production / complement component C5a receptor activity / negative regulation of neutrophil chemotaxis / complement receptor mediated signaling pathway / negative regulation of interleukin-6 production / negative regulation of tumor necrosis factor production / Regulation of Complement cascade / basal plasma membrane / Peptide ligand-binding receptors / chemotaxis ...regulation of interleukin-8 production / complement component C5a receptor activity / negative regulation of neutrophil chemotaxis / complement receptor mediated signaling pathway / negative regulation of interleukin-6 production / negative regulation of tumor necrosis factor production / Regulation of Complement cascade / basal plasma membrane / Peptide ligand-binding receptors / chemotaxis / G protein-coupled receptor activity / apical part of cell / phospholipase C-activating G protein-coupled receptor signaling pathway / positive regulation of cytosolic calcium ion concentration / basolateral plasma membrane / inflammatory response / plasma membrane
Similarity search - Function
Anaphylatoxin chemotactic receptor, C3a/C5a1/C5a2 / Formyl peptide receptor-related / 7 transmembrane receptor (rhodopsin family) / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile.
Similarity search - Domain/homology
C5a anaphylatoxin chemotactic receptor 2
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.06 Å
AuthorsTiwari D / Sano FK / Yadav MK / Sawada K / Ganguly M / Mishra S / Dalal A / Banerjee R / Nureki O / Shukla AK
Funding support United Kingdom, India, 3 items
OrganizationGrant numberCountry
Wellcome TrustIA/S/20/1/504916 United Kingdom
Science and Engineering Research Board (SERB)IPA/2020/000405 India
Science and Engineering Research Board (SERB)CRG/2022/002646 India
CitationJournal: Mol Cell / Year: 2026
Title: Molecular mechanisms of naturally encoded signaling bias at the complement anaphylatoxin receptors.
Authors: Divyanshu Tiwari / Kazuhiro Sawada / Annu Dalal / Sudha Mishra / Xaria X Li / Joshua C Dent / Kiae Kim / Manish K Yadav / Nabarun Roy / Manisankar Ganguly / Nilanjana Banerjee / Tomasz ...Authors: Divyanshu Tiwari / Kazuhiro Sawada / Annu Dalal / Sudha Mishra / Xaria X Li / Joshua C Dent / Kiae Kim / Manish K Yadav / Nabarun Roy / Manisankar Ganguly / Nilanjana Banerjee / Tomasz Maciej Stepniewski / Donghoon Ahn / Kohei Yamaguchi / Hidetaka S Oshima / Kana Hashimoto / Jenny N Fung / Titaya Lerskiatiphanich / Cedric S Cui / John D Lee / Jana Selent / Asuka Inoue / Richard J Clark / Ka Young Chung / Ramanuj Banerjee / Fumiya K Sano / Trent M Woodruff / Osamu Nureki / Arun K Shukla /
Abstract: The conceptual framework of biased agonism has greatly impacted our understanding of G-protein-coupled receptor (GPCR) signaling, regulatory paradigms, and drug discovery efforts. Here, we present ...The conceptual framework of biased agonism has greatly impacted our understanding of G-protein-coupled receptor (GPCR) signaling, regulatory paradigms, and drug discovery efforts. Here, we present fundamental molecular and structural insights into intrinsic bias encoded at the human and mouse complement anaphylatoxin C5a receptors, namely C5aR1 and C5aR2. We discover that a naturally occurring version of C5a, i.e., C5a, exhibits a robust G-protein-coupling bias at C5aR1 with attenuated β-arrestin (βarr) recruitment, which originates from a distinct conformation of TM7 and helix 8 in the receptor, leading to inefficient GRK recruitment and phosphorylation. We also determine a series of cryo-electron microscopy (cryo-EM) structures of C5aR2, a naturally encoded βarr-biased receptor, which uncover key differences in anaphylatoxin recognition by C5aR2 relative to C5aR1. These structural snapshots also uncover a shallower cytoplasmic pocket in C5aR2 with a hydrophobic interior, which is likely incompatible with efficient G-protein coupling, leading to intrinsic bias. Our findings illuminate the molecular basis of naturally encoded signaling bias at GPCRs, with direct implications for therapeutic design.
History
DepositionMay 22, 2025-
Header (metadata) releaseJul 1, 2026-
Map releaseJul 1, 2026-
UpdateJul 15, 2026-
Current statusJul 15, 2026Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_64761.png

Downloads & links

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Map

FileDownload / File: emd_64761.map.gz / Format: CCP4 / Size: 52.7 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.)
1.11 Å/pix.
x 240 pix.
= 265.608 Å		1.11 Å/pix.
x 240 pix.
= 265.608 Å		1.11 Å/pix.
x 240 pix.
= 265.608 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.1067 Å
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Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0686
Minimum - Maximum-0.61426556 - 0.94328004
Average (Standard dev.)0.00016209272 (±0.0140737295)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions240240240
Spacing240240240
CellA=B=C: 265.60797 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_64761_half_map_1.map
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Half map: #1

Fileemd_64761_half_map_2.map
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Sample components

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Entire : C5aR2 bound to C5a-pep

EntireName: C5aR2 bound to C5a-pep
Components
  • Complex: C5aR2 bound to C5a-pep
    • Protein or peptide: C5a-pep ligand
    • Protein or peptide: C5a anaphylatoxin chemotactic receptor 2

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Supramolecule #1: C5aR2 bound to C5a-pep

SupramoleculeName: C5aR2 bound to C5a-pep / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: C5a-pep ligand

MacromoleculeName: C5a-pep ligand / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 869.148 Da
SequenceString:
(MEA)KP(ZAL)(ALC)(DAR)

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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: 42.014789 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MGKTIIALSY IFCLVFADYK DDDDAANFTP VNGSSGNQSV RLVTSSSLEV LFQGPGSGND SVSYEYGDYS DLSDRPVDCL DGACLAIDP LRVAPLPLYA AIFLVGVPGN AMVAWVAGKV ARRRVGATWL LHLAVADLLC CLSLPILAVP IARGGHWPYG A VGCRALPS ...String:
MGKTIIALSY IFCLVFADYK DDDDAANFTP VNGSSGNQSV RLVTSSSLEV LFQGPGSGND SVSYEYGDYS DLSDRPVDCL DGACLAIDP LRVAPLPLYA AIFLVGVPGN AMVAWVAGKV ARRRVGATWL LHLAVADLLC CLSLPILAVP IARGGHWPYG A VGCRALPS IILLTMYASV LLLAALSADL CFLALGPAWW STVQRACGVQ VACGAAWTLA LLLTVPSAIY RRLHQEHFPA RL QCVVDYG GSSSTENAVT AIRFLFGFLG PLVAVASCHS ALLCWAARRC RPLGTAIVVG FFVCWAPYHL LGLVLTVAAP NSA LLARAL RAEPLIVGLA LAHSCLNPML FLYFGRAQLR RSLPAACHWA LRESQGQDES VDSKKSTSHD LVSEMEV

UniProtKB: C5a anaphylatoxin chemotactic receptor 2

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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 BIOQUANTUM (6k x 4k) / Average electron dose: 63.1 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.6 µm / Nominal defocus min: 0.8 µm
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionSoftware - Name: cryoSPARC (ver. 4.6.2) / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: INSILICO MODEL
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.06 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4.6.2) / Number images used: 162835
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

Initial modelChain - Source name: SwissModel / Chain - Initial model type: in silico model
RefinementSpace: REAL / Protocol: FLEXIBLE FIT
Output model

PDB-9v3y:
Structure of C5a anaphylatoxin chemotactic receptor 2, C5aR2 bound to C5a-pep

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