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- PDB-9ipy: Structure of JR14a-bound human C3aR -

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Entry
Database: PDB / ID: 9ipy
TitleStructure of JR14a-bound human C3aR
ComponentsC3a anaphylatoxin chemotactic receptor,Soluble cytochrome b562
KeywordsMEMBRANE PROTEIN / GPCR
Function / homology
Function and homology information


complement component C3a receptor activity / complement component C5a receptor activity / complement receptor mediated signaling pathway / positive regulation of neutrophil chemotaxis / blood circulation / azurophil granule membrane / positive regulation of macrophage chemotaxis / positive regulation of vascular endothelial growth factor production / Purinergic signaling in leishmaniasis infection / specific granule membrane ...complement component C3a receptor activity / complement component C5a receptor activity / complement receptor mediated signaling pathway / positive regulation of neutrophil chemotaxis / blood circulation / azurophil granule membrane / positive regulation of macrophage chemotaxis / positive regulation of vascular endothelial growth factor production / Purinergic signaling in leishmaniasis infection / specific granule membrane / Peptide ligand-binding receptors / Regulation of Complement cascade / calcium-mediated signaling / electron transport chain / G protein-coupled receptor activity / positive regulation of angiogenesis / chemotaxis / positive regulation of cytosolic calcium ion concentration / G alpha (i) signalling events / phospholipase C-activating G protein-coupled receptor signaling pathway / periplasmic space / electron transfer activity / G protein-coupled receptor signaling pathway / iron ion binding / inflammatory response / heme binding / Neutrophil degranulation / plasma membrane
Similarity search - Function
C3a anaphylatoxin chemotactic receptor / Anaphylatoxin chemotactic receptor, C3a/C5a1/C5a2 / Formyl peptide receptor-related / Cytochrome b562 / Cytochrome b562 / Cytochrome c/b562 / 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)
Similarity search - Domain/homology
: / Soluble cytochrome b562 / C3a anaphylatoxin chemotactic receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
Escherichia coli (E. coli)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.5 Å
AuthorsKim, J. / Ko, S. / Choi, H.-J.
Funding support Korea, Republic Of, 1items
OrganizationGrant numberCountry
National Research Foundation (NRF, Korea)2023R1A2C300420512 Korea, Republic Of
CitationJournal: EMBO J / Year: 2025
Title: Structural insights into small-molecule agonist recognition and activation of complement receptor C3aR.
Authors: Jinuk Kim / Saebom Ko / Chulwon Choi / Jungnam Bae / Hyeonsung Byeon / Chaok Seok / Hee-Jung Choi /
Abstract: The complement system plays crucial roles in innate immunity and inflammatory responses. The anaphylatoxin C3a mediates pro-inflammatory and chemotactic functions through the G protein-coupled ...The complement system plays crucial roles in innate immunity and inflammatory responses. The anaphylatoxin C3a mediates pro-inflammatory and chemotactic functions through the G protein-coupled receptor C3aR. While the active structure of the C3a-C3aR-G complex has been determined, the inactive conformation and activation mechanism of C3aR remain elusive. Here we report the cryo-EM structure of ligand-free, G protein-free C3aR, providing insights into its inactive conformation. In addition, we determine the structures of C3aR in complex with the synthetic small-molecule agonist JR14a in two distinct conformational states: a G protein-free intermediate, and a fully active G-bound state. The structure of the active JR14a-bound C3aR reveals that JR14a engages in highly conserved interactions with C3aR, similar to the binding of the C-terminal pentapeptide of C3a, along with JR14a-specific interactions. Structural comparison of C3aR in the apo, intermediate, and fully active states provides novel insights into the conformational landscape and activation mechanism of C3aR and defines a molecular basis explaining its high basal activity. Our results may aid in the rational design of therapeutics targeting complement-related inflammatory disorders.
History
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
R: C3a anaphylatoxin chemotactic receptor,Soluble cytochrome b562
hetero molecules


Theoretical massNumber of molelcules
Total (without water)69,1422
Polymers68,6081
Non-polymers5331
Water00
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein C3a anaphylatoxin chemotactic receptor,Soluble cytochrome b562 / C3AR / C3a-R / Cytochrome b-562


Mass: 68608.289 Da / Num. of mol.: 1 / Mutation: M1012W/H1107I
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human), (gene. exp.) Escherichia coli (E. coli)
Gene: C3AR1, AZ3B, C3R1, HNFAG09, cybC / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q16581, UniProt: P0ABE7
#2: Chemical ChemComp-A1D9A / (2~{S})-5-[bis(azanyl)methylideneamino]-2-[[5-[bis(4-chlorophenyl)methyl]-3-methyl-thiophen-2-yl]carbonylamino]pentanoic acid / JR14a


Mass: 533.470 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H26Cl2N4O3S / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
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: C3aR-BRIL / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
11Homo sapiens (human)9606
21Escherichia coli (E. coli)562
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.5
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: 1700 nm / Nominal defocus min: 900 nm
Image recordingElectron dose: 60.8 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM software
IDNameCategory
1cryoSPARCparticle selection
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 342058 / Symmetry type: POINT

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