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- PDB-9v35: Structure of C5a anaphylatoxin chemotactic receptor 2, C5aR2 in t... -

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Basic information

Entry
Database: PDB / ID: 9v35
TitleStructure of C5a anaphylatoxin chemotactic receptor 2, C5aR2 in the Apo state
ComponentsC5a anaphylatoxin chemotactic receptor 2
KeywordsSIGNALING PROTEIN / G protein coupled receptor / G protein / Membrane protein / Immunite system
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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.97 Å
AuthorsTiwari, D. / Sano, F.K. / Yadav, M.K. / Sawada, K. / Ganguly, M. / Mishra, S. / Dalal, A. / Banerjee, R. / Nureki, O. / 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
DepositionMay 21, 2025Deposition 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
Revision 1.1Jul 15, 2026Group: Data collection / Database references / Category: citation / em_admin
Item: _citation.journal_volume / _citation.page_first / _em_admin.last_update
Revision 1.1Jul 15, 2026Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Database references / Experimental summary / Data content type: EM metadata / EM metadata / Category: citation / em_admin / Data content type: EM metadata / EM metadata / EM metadata
Item: _citation.journal_volume / _citation.page_first / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: C5a anaphylatoxin chemotactic receptor 2


Theoretical massNumber of molelcules
Total (without water)42,0151
Polymers42,0151
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: 42014.789 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: C5AR2, C5L2, GPR77 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q9P296
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: C5aR2 in the Apo state / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
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: 62.1 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
4cryoSPARC4.6.2CTF correction
7Coot0.9.6model fitting
9cryoSPARC4.6.2initial Euler assignment
10cryoSPARC4.6.2final Euler assignment
11cryoSPARC4.6.2classification
12cryoSPARC4.6.23D reconstruction
13PHENIXmodel refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 2.97 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 117521 / Symmetry type: POINT
Atomic model buildingProtocol: FLEXIBLE FIT / Space: REAL
Atomic model buildingSource name: SwissModel / Type: in silico model

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