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- PDB-8i9l: Structure of C3a-C3aR-Go complex (Composite map) -

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Entry
Database: PDB / ID: 8i9l
TitleStructure of C3a-C3aR-Go complex (Composite map)
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Antibody fragment - ScFv16
  • C3a anaphylatoxin
  • C3a anaphylatoxin chemotactic receptor
KeywordsSIGNALING PROTEIN/IMMUNE SYSTEM / GPCR / G protein / SIGNALING PROTEIN-IMMUNE SYSTEM complex
Function / homology
Function and homology information


complement component C3a receptor activity / complement component C5a receptor activity / C5L2 anaphylatoxin chemotactic receptor binding / oviduct epithelium development / regulation of triglyceride biosynthetic process / positive regulation of activation of membrane attack complex / vertebrate eye-specific patterning / positive regulation of apoptotic cell clearance / complement-mediated synapse pruning / Alternative complement activation ...complement component C3a receptor activity / complement component C5a receptor activity / C5L2 anaphylatoxin chemotactic receptor binding / oviduct epithelium development / regulation of triglyceride biosynthetic process / positive regulation of activation of membrane attack complex / vertebrate eye-specific patterning / positive regulation of apoptotic cell clearance / complement-mediated synapse pruning / Alternative complement activation / positive regulation of lipid storage / positive regulation of phagocytosis, engulfment / Activation of C3 and C5 / positive regulation of G protein-coupled receptor signaling pathway / complement receptor mediated signaling pathway / mu-type opioid receptor binding / positive regulation of type IIa hypersensitivity / corticotropin-releasing hormone receptor 1 binding / positive regulation of D-glucose transmembrane transport / complement-dependent cytotoxicity / complement activation / complement activation, alternative pathway / vesicle docking involved in exocytosis / positive regulation of neutrophil chemotaxis / blood circulation / azurophil granule membrane / endopeptidase inhibitor activity / neuron remodeling / G protein-coupled dopamine receptor signaling pathway / regulation of heart contraction / positive regulation of macrophage chemotaxis / parallel fiber to Purkinje cell synapse / amyloid-beta clearance / B cell activation / positive regulation of vascular endothelial growth factor production / complement activation, classical pathway / postsynaptic modulation of chemical synaptic transmission / negative regulation of insulin secretion / Purinergic signaling in leishmaniasis infection / specific granule membrane / G protein-coupled serotonin receptor binding / adenylate cyclase-inhibiting serotonin receptor signaling pathway / adenylate cyclase regulator activity / muscle contraction / Peptide ligand-binding receptors / GABA-ergic synapse / Regulation of Complement cascade / fatty acid metabolic process / locomotory behavior / Post-translational protein phosphorylation / response to bacterium / calcium-mediated signaling / G protein-coupled receptor activity / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / G-protein beta/gamma-subunit complex binding / Olfactory Signaling Pathway / Activation of the phototransduction cascade / positive regulation of receptor-mediated endocytosis / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / G protein-coupled acetylcholine receptor signaling pathway / G-protein activation / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through CDC42 / Glucagon signaling in metabolic regulation / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / ADP signalling through P2Y purinoceptor 12 / Sensory perception of sweet, bitter, and umami (glutamate) taste / photoreceptor disc membrane / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / positive regulation of angiogenesis / Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell / Vasopressin regulates renal water homeostasis via Aquaporins / chemotaxis / G alpha (z) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / azurophil granule lumen / ADORA2B mediated anti-inflammatory cytokines production / cellular response to catecholamine stimulus / ADP signalling through P2Y purinoceptor 1 / G beta:gamma signalling through PI3Kgamma / adenylate cyclase-activating dopamine receptor signaling pathway / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / GPER1 signaling / Inactivation, recovery and regulation of the phototransduction cascade / cellular response to prostaglandin E stimulus / G-protein beta-subunit binding / heterotrimeric G-protein complex / G alpha (12/13) signalling events / sensory perception of taste / extracellular vesicle / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / G protein activity
Similarity search - Function
C3a anaphylatoxin chemotactic receptor / Anaphylatoxin chemotactic receptor, C3a/C5a1/C5a2 / Complement C3-like, NTR domain / : / : / Complement component 3, CUB domain, second segment / Complement component 3, CUB domain, first segment / Formyl peptide receptor-related / Alpha-2-macroglobulin, conserved site / Alpha-2-macroglobulin family thiolester region signature. ...C3a anaphylatoxin chemotactic receptor / Anaphylatoxin chemotactic receptor, C3a/C5a1/C5a2 / Complement C3-like, NTR domain / : / : / Complement component 3, CUB domain, second segment / Complement component 3, CUB domain, first segment / Formyl peptide receptor-related / Alpha-2-macroglobulin, conserved site / Alpha-2-macroglobulin family thiolester region signature. / Complement C3/4/5, macroglobulin domain MG1 / Macroglobulin domain MG1 / Anaphylatoxin, complement system domain / : / Anaphylatoxin domain signature. / Alpha-macro-globulin thiol-ester bond-forming region / 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 / Netrin domain / NTR domain profile. / Alpha-macroglobulin, receptor-binding / Alpha-macroglobulin, receptor-binding domain superfamily / Macroglobulin domain MG3 / : / A-macroglobulin receptor binding domain / Macroglobulin domain MG3 / A-macroglobulin receptor / Tissue inhibitor of metalloproteinases-like, OB-fold / 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 / Terpenoid cyclases/protein prenyltransferase alpha-alpha toroid / G-protein alpha subunit, group I / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G-alpha domain profile. / G protein alpha subunit / G-protein, gamma subunit / G-protein gamma subunit domain profile. / G-protein gamma-like domain / G-protein gamma-like domain superfamily / GGL domain / G protein gamma subunit-like motifs / GGL domain / Guanine nucleotide-binding protein, beta subunit / G-protein, beta subunit / 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) / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD domain, G-beta repeat / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / Immunoglobulin-like fold / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Complement C3 / Guanine nucleotide-binding protein G(o) subunit alpha / Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / C3a anaphylatoxin chemotactic receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
Mus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.18 Å
AuthorsYadav, M.K. / Yadav, R. / Maharana, J. / Sarma, P. / Banerjee, R. / Shukla, A.K. / Gati, C.
Funding support India, United Kingdom, 4items
OrganizationGrant numberCountry
Department of Biotechnology (DBT, India)BT/PR29041/BRB/10/1697/2018 India
Wellcome TrustIA/S/20/1/504916 United Kingdom
Science and Engineering Research Board (SERB)SPR/2020/000408 India
Science and Engineering Research Board (SERB)IPA/2020/000405 India
CitationJournal: Cell / Year: 2023
Title: Molecular basis of anaphylatoxin binding, activation, and signaling bias at complement receptors.
Authors: Manish K Yadav / Jagannath Maharana / Ravi Yadav / Shirsha Saha / Parishmita Sarma / Chahat Soni / Vinay Singh / Sayantan Saha / Manisankar Ganguly / Xaria X Li / Samanwita Mohapatra / Sudha ...Authors: Manish K Yadav / Jagannath Maharana / Ravi Yadav / Shirsha Saha / Parishmita Sarma / Chahat Soni / Vinay Singh / Sayantan Saha / Manisankar Ganguly / Xaria X Li / Samanwita Mohapatra / Sudha Mishra / Htet A Khant / Mohamed Chami / Trent M Woodruff / Ramanuj Banerjee / Arun K Shukla / Cornelius Gati /
Abstract: The complement system is a critical part of our innate immune response, and the terminal products of this cascade, anaphylatoxins C3a and C5a, exert their physiological and pathophysiological ...The complement system is a critical part of our innate immune response, and the terminal products of this cascade, anaphylatoxins C3a and C5a, exert their physiological and pathophysiological responses primarily via two GPCRs, C3aR and C5aR1. However, the molecular mechanism of ligand recognition, activation, and signaling bias of these receptors remains mostly elusive. Here, we present nine cryo-EM structures of C3aR and C5aR1 activated by their natural and synthetic agonists, which reveal distinct binding pocket topologies of complement anaphylatoxins and provide key insights into receptor activation and transducer coupling. We also uncover the structural basis of a naturally occurring mechanism to dampen the inflammatory response of C5a via proteolytic cleavage of the terminal arginine and the G-protein signaling bias elicited by a peptide agonist of C3aR identified here. In summary, our study elucidates the innerworkings of the complement anaphylatoxin receptors and should facilitate structure-guided drug discovery to target these receptors in a spectrum of disorders.
History
DepositionFeb 7, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Oct 18, 2023Provider: repository / Type: Initial release
Revision 1.1Nov 1, 2023Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name
Revision 1.2Nov 8, 2023Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Oct 23, 2024Group: Data collection / Structure summary
Category: em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
B: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
A: Guanine nucleotide-binding protein G(o) subunit alpha
G: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
H: Antibody fragment - ScFv16
C: C3a anaphylatoxin chemotactic receptor
D: C3a anaphylatoxin


Theoretical massNumber of molelcules
Total (without water)169,9796
Polymers169,9796
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Guanine nucleotide-binding protein ... , 3 types, 3 molecules BAG

#1: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 38534.062 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNB1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P62873
#2: Protein Guanine nucleotide-binding protein G(o) subunit alpha


Mass: 28193.939 Da / Num. of mol.: 1 / Fragment: UNP residues 4-57,UNP residues 182-354 / Mutation: G42D, E43N
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNAO1 / Production host: Escherichia coli (E. coli) / References: UniProt: P09471
#3: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / G gamma-I


Mass: 7861.143 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNG2 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P59768

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Protein , 2 types, 2 molecules CD

#5: Protein C3a anaphylatoxin chemotactic receptor / C3AR / C3a-R


Mass: 59808.422 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: C3AR1, AZ3B, C3R1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q16581
#6: Protein C3a anaphylatoxin


Mass: 9114.731 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: C3, CPAMD1 / Production host: Escherichia coli (E. coli) / References: UniProt: P01024

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Antibody , 1 types, 1 molecules H

#4: Antibody Antibody fragment - ScFv16


Mass: 26466.486 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Escherichia coli (E. coli)

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Details

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

Component
IDNameTypeEntity IDParent-IDSource
1Structure of C3a-C3aR-Go complexCOMPLEXall0MULTIPLE SOURCES
2Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1COMPLEX#11RECOMBINANT
3Guanine nucleotide-binding protein G(o) subunit alphaCOMPLEX#21RECOMBINANT
4Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2COMPLEX#31RECOMBINANT
5Antibody fragment - ScFv16COMPLEX#41RECOMBINANT
6C3a anaphylatoxin chemotactic receptorCOMPLEX#51RECOMBINANT
7C3a LigandCOMPLEX#61RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
22Homo sapiens (human)9606
33Homo sapiens (human)9606
43Homo sapiens (human)9606
54Homo sapiens (human)9606
65Mus musculus (house mouse)10090
76Homo sapiens (human)9606
87Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
22Spodoptera frugiperda (fall armyworm)7108
33Escherichia coli (E. coli)562
43Escherichia coli (E. coli)562
54Escherichia coli (E. coli)562
65Escherichia coli (E. coli)562
76Spodoptera frugiperda (fall armyworm)7108
87Escherichia coli (E. coli)562
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

MicroscopyModel: TFS GLACIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 3000 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 50 e/Å2 / Detector mode: COUNTING / Film or detector model: FEI FALCON IV (4k x 4k) / Num. of real images: 20051
Image scansMovie frames/image: 40

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Processing

EM software
IDNameVersionCategory
7Cootmodel fitting
11cryoSPARC4classification
12cryoSPARC43D reconstruction
13PHENIXmodel refinement
CTF correctionType: NONE
Particle selectionNum. of particles selected: 9449228
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.18 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 418953 / Symmetry type: POINT
Atomic model buildingProtocol: FLEXIBLE FIT / Space: REAL
Atomic model buildingPDB-ID: 8I95

8i95


Accession code: 8I95 / Source name: PDB / Type: experimental model

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