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- PDB-8i97: Structure of Apo-C3aR-Go complex (Glacios) -

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Basic information

Entry
Database: PDB / ID: 8i97
TitleStructure of Apo-C3aR-Go complex (Glacios)
Components
  • Antibody fragment - ScFv16
  • C3a anaphylatoxin chemotactic receptor
  • 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
  • Guanine nucleotide-binding protein G(o) subunit alpha
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 / complement receptor mediated signaling pathway / mu-type opioid receptor binding / corticotropin-releasing hormone receptor 1 binding / vesicle docking involved in exocytosis / positive regulation of neutrophil chemotaxis / blood circulation / azurophil granule membrane / G protein-coupled dopamine receptor signaling pathway ...complement component C3a receptor activity / complement component C5a receptor activity / complement receptor mediated signaling pathway / mu-type opioid receptor binding / corticotropin-releasing hormone receptor 1 binding / vesicle docking involved in exocytosis / positive regulation of neutrophil chemotaxis / blood circulation / azurophil granule membrane / G protein-coupled dopamine receptor signaling pathway / regulation of heart contraction / positive regulation of macrophage chemotaxis / parallel fiber to Purkinje cell synapse / positive regulation of vascular endothelial growth factor production / 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 / muscle contraction / adenylate cyclase-inhibiting serotonin receptor signaling pathway / adenylate cyclase regulator activity / Peptide ligand-binding receptors / GABA-ergic synapse / Regulation of Complement cascade / locomotory behavior / calcium-mediated signaling / G protein-coupled receptor activity / G-protein beta/gamma-subunit complex binding / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / Olfactory Signaling Pathway / Activation of the phototransduction cascade / 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 / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / positive regulation of angiogenesis / G alpha (z) signalling events / chemotaxis / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / 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 / cellular response to prostaglandin E stimulus / Inactivation, recovery and regulation of the phototransduction cascade / 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) / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / G protein activity / presynaptic membrane / cell body / GTPase binding / Ca2+ pathway / retina development in camera-type eye / positive regulation of cytosolic calcium ion concentration / fibroblast proliferation / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (i) signalling events / Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement / G alpha (s) signalling events / G alpha (q) signalling events / postsynaptic membrane / Ras protein signal transduction / cell population proliferation / Extra-nuclear estrogen signaling / inflammatory response / G protein-coupled receptor signaling pathway / lysosomal membrane / GTPase activity / dendrite / synapse / Neutrophil degranulation / protein-containing complex binding / GTP binding / glutamatergic synapse / signal transduction / extracellular exosome
Similarity search - Function
C3a anaphylatoxin chemotactic receptor / Anaphylatoxin chemotactic receptor, C3a/C5a1/C5a2 / Formyl peptide receptor-related / 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 ...C3a anaphylatoxin chemotactic receptor / Anaphylatoxin chemotactic receptor, C3a/C5a1/C5a2 / Formyl peptide receptor-related / 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 / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
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: 3.19 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 6, 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 1.3Nov 6, 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
C: C3a anaphylatoxin chemotactic receptor
A: Guanine nucleotide-binding protein G(o) subunit alpha
B: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
G: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
H: Antibody fragment - ScFv16


Theoretical massNumber of molelcules
Total (without water)160,8645
Polymers160,8645
Non-polymers00
Water00
1


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

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Components

#1: 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, HNFAG09 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q16581
#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,A227D,G230D,I332A,V35I
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(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
#4: 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
#5: 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)
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-IDSourceDetails
1Structure of Apo-C3aR-Go complex (Glacios)COMPLEXall0MULTIPLE SOURCES
2C3a anaphylatoxin chemotactic receptorCOMPLEX#11RECOMBINANT
3Guanine nucleotide-binding protein G(o) subunit alphaCOMPLEX#21RECOMBINANTThis is a variant of Guanine nucleotide-binding protein G(o) subunit alpha called the "mini G(o) alpha"
4Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1COMPLEX#31RECOMBINANT
5Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2COMPLEX#41RECOMBINANT
6Antibody fragment - ScFv16COMPLEX#51RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
22Homo sapiens (human)9606
33Homo sapiens (human)9606
54Homo sapiens (human)9606
65Homo sapiens (human)9606
76Mus musculus (house mouse)10090
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
22Spodoptera frugiperda (fall armyworm)7108
33Escherichia coli (E. coli)562
54Spodoptera frugiperda (fall armyworm)7108
65Spodoptera frugiperda (fall armyworm)7108
76Escherichia 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: 4611
Image scansMovie frames/image: 40

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Processing

EM software
IDNameVersionCategory
7Cootmodel fitting
9PHENIXmodel refinement
12cryoSPARC3.3.2classification
13cryoSPARC3.3.23D reconstruction
CTF correctionType: NONE
Particle selectionNum. of particles selected: 4543010
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.19 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 464408 / 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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