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

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Basic information

Entry
Database: PDB / ID: 25if
TitleStructure of mC5aR2 in complex with mC5a-desArg (Monomer)
Components
  • C5a anaphylatoxin chemotactic receptor 2
  • Complement C5
KeywordsSIGNALING PROTEIN / G protein coupled receptor / G protein / Membrane protein / Immunite system
Function / homology
Function and homology information


Terminal pathway of complement / C5a anaphylatoxin chemotactic receptor binding / Activation of C3 and C5 / complement receptor activity / negative regulation of norepinephrine secretion / negative regulation of dopamine secretion / Regulation of Complement cascade / membrane attack complex / Peptide ligand-binding receptors / complement activation, lectin pathway ...Terminal pathway of complement / C5a anaphylatoxin chemotactic receptor binding / Activation of C3 and C5 / complement receptor activity / negative regulation of norepinephrine secretion / negative regulation of dopamine secretion / Regulation of Complement cascade / membrane attack complex / Peptide ligand-binding receptors / complement activation, lectin pathway / inflammatory response to wounding / leukocyte migration involved in inflammatory response / G alpha (i) signalling events / complement activation, GZMK pathway / negative regulation of macrophage chemotaxis / other organism cell membrane / positive regulation of chemotaxis / glomerulus development / neutrophil homeostasis / transmembrane transporter complex / leukocyte chemotaxis / complement activation, alternative pathway / complement activation / chemokine activity / endopeptidase inhibitor activity / complement activation, classical pathway / positive regulation of vascular endothelial growth factor production / positive regulation of chemokine production / kidney development / G protein-coupled receptor activity / chemotaxis / intracellular calcium ion homeostasis / positive regulation of angiogenesis / positive regulation of cytosolic calcium ion concentration / killing of cells of another organism / in utero embryonic development / receptor ligand activity / : / 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 / Tissue inhibitor of metalloproteinases-like, OB-fold / 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 / 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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.42 Å
AuthorsTiwari, D. / Ganguly, M. / Banerjee, R. / Shukla, A.K.
Funding support United Kingdom, India, 3items
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, 2026Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jul 1, 2026Provider: repository / Type: Initial release
Revision 1.0Jul 1, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Jul 1, 2026Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Jul 1, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jul 1, 2026Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jul 1, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Jul 1, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: C5a anaphylatoxin chemotactic receptor 2
B: Complement C5


Theoretical massNumber of molelcules
Total (without water)52,8992
Polymers52,8992
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein C5a anaphylatoxin chemotactic receptor 2 / Complement component 5a receptor 2 / G-protein coupled receptor 77


Mass: 44137.070 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: C5ar2, Gpr77 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: E9QQ21
#2: Protein Complement C5 / Hemolytic complement


Mass: 8762.245 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: C5, Hc / Production host: Escherichia coli (E. coli) / References: UniProt: P06684
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: mC5aR2 bound to mC5a-desArg (Monomer) / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Source (natural)Organism: Mus musculus (house mouse)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1600 nm / Nominal defocus min: 800 nm
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 75 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM software
IDNameVersionCategory
1cryoSPARC4.6.2particle selection
2EPUimage acquisition
4cryoSPARC4.5.3CTF correction
7Coot0.9.6model fitting
9cryoSPARC4.5.3initial Euler assignment
10cryoSPARC4.5.3final Euler assignment
11cryoSPARC4.5.3classification
12cryoSPARC4.5.33D reconstruction
13PHENIXmodel refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.42 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 285775 / Symmetry type: POINT
Atomic model buildingProtocol: FLEXIBLE FIT / Space: REAL
Atomic model buildingPDB-ID: 9WDI

9wdi


Accession code: 9WDI / Source name: PDB / Type: experimental model
RefinementHighest resolution: 3.42 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)

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