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- EMDB-80132: Structure of mC5aR2 in complex with mC5a-desArg (Monomer) -

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Basic information

Entry
Database: EMDB / ID: EMD-80132
TitleStructure of mC5aR2 in complex with mC5a-desArg (Monomer)
Map data
Sample
  • Complex: mC5aR2 bound to mC5a-desArg (Monomer)
    • Protein or peptide: C5a anaphylatoxin chemotactic receptor 2
    • Protein or peptide: Complement C5
KeywordsG protein coupled receptor / G protein / Membrane protein / Immunite system / SIGNALING PROTEIN
Function / homology
Function and homology information


Terminal pathway of complement / Activation of C3 and C5 / complement receptor activity / Regulation of Complement cascade / Peptide ligand-binding receptors / membrane attack complex / complement activation, lectin pathway / G alpha (i) signalling events / complement activation, GZMK pathway / other organism cell membrane ...Terminal pathway of complement / Activation of C3 and C5 / complement receptor activity / Regulation of Complement cascade / Peptide ligand-binding receptors / membrane attack complex / complement activation, lectin pathway / G alpha (i) signalling events / complement activation, GZMK pathway / other organism cell membrane / complement activation, alternative pathway / endopeptidase inhibitor activity / complement activation, classical pathway / chemotaxis / G protein-coupled receptor activity / positive regulation of angiogenesis / killing of cells of another organism / inflammatory response / : / plasma membrane
Similarity search - Function
: / Complement component 5, CUB domain / Anaphylatoxin chemotactic receptor, C3a/C5a1/C5a2 / Formyl peptide receptor-related / Complement C3/4/5, macroglobulin domain MG1 / Macroglobulin domain MG1 / Anaphylatoxin domain signature. / Anaphylatoxin, complement system / Anaphylatoxin/fibulin / Anaphylotoxin-like domain ...: / Complement component 5, CUB domain / Anaphylatoxin chemotactic receptor, C3a/C5a1/C5a2 / Formyl peptide receptor-related / Complement C3/4/5, macroglobulin domain MG1 / Macroglobulin domain MG1 / Anaphylatoxin domain signature. / Anaphylatoxin, complement system / Anaphylatoxin/fibulin / Anaphylotoxin-like domain / Anaphylatoxin domain profile. / Anaphylatoxin homologous domain / 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 / 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
C5a anaphylatoxin chemotactic receptor 2 / Complement C5
Similarity search - Component
Biological speciesMus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.42 Å
AuthorsTiwari D / Ganguly M / Banerjee R / Shukla AK / Mishra S / Dalal A / Nureki O
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
DepositionApr 6, 2026-
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_80132.png

Downloads & links

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Map

FileDownload / File: emd_80132.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

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AxesX (Sec.)Y (Row.)Z (Col.)
0.91 Å/pix.
x 256 pix.
= 233.201 Å		0.91 Å/pix.
x 256 pix.
= 233.201 Å		0.91 Å/pix.
x 256 pix.
= 233.201 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.91094 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 7.36
Minimum - Maximum-28.242972999999999 - 72.885050000000007
Average (Standard dev.)-0.000000000001137 (±1.0)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderZYX
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 233.20064 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_80132_half_map_1.map
Projections & Slices
AxesZYX

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Half map: #1

Fileemd_80132_half_map_2.map
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Sample components

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Entire : mC5aR2 bound to mC5a-desArg (Monomer)

EntireName: mC5aR2 bound to mC5a-desArg (Monomer)
Components
  • Complex: mC5aR2 bound to mC5a-desArg (Monomer)
    • Protein or peptide: C5a anaphylatoxin chemotactic receptor 2
    • Protein or peptide: Complement C5

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Supramolecule #1: mC5aR2 bound to mC5a-desArg (Monomer)

SupramoleculeName: mC5aR2 bound to mC5a-desArg (Monomer) / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Mus musculus (house mouse)

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Macromolecule #1: C5a anaphylatoxin chemotactic receptor 2

MacromoleculeName: C5a anaphylatoxin chemotactic receptor 2 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 44.13707 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MGKTIIALSY IFCLVFADYK DDDDAANFTP VNGSSGNQSV RLVTSSSLEV LFQGPGSMNH TTSEYYDYEY DHEHYSDLPD VPVDCPAGT CFTSDVYLIV LLVLYAAVFL VGVPGNTLVA WVTWKESRHR LGASWFLHLT MADLLCCVSL PFLAVPIAQK G HWPYGAAG ...String:
MGKTIIALSY IFCLVFADYK DDDDAANFTP VNGSSGNQSV RLVTSSSLEV LFQGPGSMNH TTSEYYDYEY DHEHYSDLPD VPVDCPAGT CFTSDVYLIV LLVLYAAVFL VGVPGNTLVA WVTWKESRHR LGASWFLHLT MADLLCCVSL PFLAVPIAQK G HWPYGAAG CWLLSSITIL SMYASVLLLT GLSGDLFLLA FRPSWKGADH RTFGVRVVQA SSWMLGLLLT VPSAVYRRLL QE HYPPRLV CGIDYGGSVS AEVAITTVRF LFGFLGPLVF MAGCHGILQR QMARRHWPLG TAVVVGFFIC WTPYHVLRVI IAA APPHSL LLARVLEAEP LFNGLALAHS ALNPIMFLYF GRKQLCKSLQ AACHWALRDP QDEESAVTKV SISTSHEMVS EMPV

UniProtKB: C5a anaphylatoxin chemotactic receptor 2

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Macromolecule #2: Complement C5

MacromoleculeName: Complement C5 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 8.762245 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
NLHLLRQKIE EQAAKYKHSV PKKCCYDGAR VNFYETCEER VARVTIGPLC IRAFNECCTI ANKIRKESPH KPVQLG

UniProtKB: Complement C5

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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: 75.0 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. 4.5.3) / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: INSILICO MODEL
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.42 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4.5.3) / Number images used: 285775
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.5.3)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.5.3)
Final 3D classificationSoftware - Name: cryoSPARC (ver. 4.5.3)
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

9wdi


Chain - Source name: PDB / Chain - Initial model type: experimental model
RefinementSpace: REAL / Protocol: FLEXIBLE FIT
Output model

PDB-25if:
Structure of mC5aR2 in complex with mC5a-desArg (Monomer)

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