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- PDB-8ia2: Structure of C5a bound human C5aR1 in complex with Go (Composite map) -

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Basic information

Entry
Database: PDB / ID: 8ia2
TitleStructure of C5a bound human C5aR1 in complex with Go (Composite map)
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Antibody fragment - ScFv16
  • C5a anaphylatoxin
  • C5a anaphylatoxin chemotactic receptor 1
KeywordsSIGNALING PROTEIN/IMMUNE SYSTEM / GPCR / G protein / SIGNALING PROTEIN-IMMUNE SYSTEM complex
Function / homology
Function and homology information


complement component C5a signaling pathway / presynapse organization / regulation of tau-protein kinase activity / complement component C5a receptor activity / response to peptidoglycan / Terminal pathway of complement / membrane attack complex / sensory perception of chemical stimulus / mu-type opioid receptor binding / Activation of C3 and C5 ...complement component C5a signaling pathway / presynapse organization / regulation of tau-protein kinase activity / complement component C5a receptor activity / response to peptidoglycan / Terminal pathway of complement / membrane attack complex / sensory perception of chemical stimulus / mu-type opioid receptor binding / Activation of C3 and C5 / complement receptor mediated signaling pathway / corticotropin-releasing hormone receptor 1 binding / negative regulation of macrophage chemotaxis / vesicle docking involved in exocytosis / complement activation, alternative pathway / positive regulation of neutrophil chemotaxis / chemokine activity / G protein-coupled dopamine receptor signaling pathway / endopeptidase inhibitor activity / regulation of heart contraction / positive regulation of macrophage chemotaxis / amyloid-beta clearance / positive regulation of vascular endothelial growth factor production / cellular defense response / negative regulation of insulin secretion / complement activation, classical pathway / G protein-coupled serotonin receptor binding / positive regulation of chemokine production / muscle contraction / neutrophil chemotaxis / Peptide ligand-binding receptors / positive regulation of epithelial cell proliferation / secretory granule membrane / Regulation of Complement cascade / locomotory behavior / astrocyte activation / G protein-coupled receptor activity / microglial cell activation / mRNA transcription by RNA polymerase II / G-protein beta/gamma-subunit complex binding / Olfactory Signaling Pathway / adenylate cyclase-modulating G protein-coupled receptor 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 / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / cognition / G beta:gamma signalling through BTK / ADP signalling through P2Y purinoceptor 12 / Sensory perception of sweet, bitter, and umami (glutamate) taste / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / photoreceptor disc membrane / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / G alpha (z) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / cellular response to catecholamine stimulus / ADORA2B mediated anti-inflammatory cytokines production / positive regulation of angiogenesis / sensory perception of taste / ADP signalling through P2Y purinoceptor 1 / G beta:gamma signalling through PI3Kgamma / adenylate cyclase-activating dopamine receptor signaling pathway / chemotaxis / 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 / extracellular vesicle / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / apical part of cell / GTPase binding / retina development in camera-type eye / Ca2+ pathway / phospholipase C-activating G protein-coupled receptor signaling pathway / positive regulation of cytosolic calcium ion concentration / cell body / G alpha (i) signalling events / fibroblast proliferation / G alpha (s) signalling events / Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement / basolateral plasma membrane / G alpha (q) signalling events / Ras protein signal transduction / killing of cells of another organism / cell population proliferation / Extra-nuclear estrogen signaling / positive regulation of ERK1 and ERK2 cascade
Similarity search - Function
Anaphylatoxin chemotactic receptor, C3a/C5a1/C5a2 / : / Complement component 5, CUB domain / Formyl peptide receptor-related / Complement C3/4/5, macroglobulin domain MG1 / Macroglobulin domain MG1 / Anaphylatoxin, complement system domain / Anaphylatoxin domain signature. / Anaphylatoxin, complement system / Anaphylatoxin/fibulin ...Anaphylatoxin chemotactic receptor, C3a/C5a1/C5a2 / : / Complement component 5, CUB domain / Formyl peptide receptor-related / Complement C3/4/5, macroglobulin domain MG1 / Macroglobulin domain MG1 / Anaphylatoxin, complement system domain / 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 / Alpha-macroglobulin, receptor-binding / Alpha-macroglobulin, receptor-binding domain superfamily / Macroglobulin domain MG4 / Macroglobulin domain MG3 / : / A-macroglobulin receptor binding domain / Macroglobulin domain MG4 / Macroglobulin domain MG3 / A-macroglobulin receptor / Netrin domain / NTR domain profile. / 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 / Tissue inhibitor of metalloproteinases-like, OB-fold / 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 C5 / Guanine nucleotide-binding protein G(o) subunit alpha / C5a anaphylatoxin chemotactic receptor 1 / 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
Similarity search - Component
Biological speciesHomo sapiens (human)
Mus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.21 Å
AuthorsYadav, M.K. / Yadav, R. / Maharana, J. / Banerjee, R. / Shukla, A.K. / Gati, C.
Funding support India, United Kingdom, 4items
OrganizationGrant numberCountry
Department of Biotechnology (DBT, India)BT/PR29041/BRB/10/1697/20 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: C5a anaphylatoxin chemotactic receptor 1
D: C5a anaphylatoxin
B: Guanine nucleotide-binding protein G(o) subunit alpha
C: 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)154,6186
Polymers154,6186
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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Protein , 2 types, 2 molecules AD

#1: Protein C5a anaphylatoxin chemotactic receptor 1 / C5a anaphylatoxin chemotactic receptor / C5a-R / C5aR


Mass: 45273.867 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: C5AR1, C5AR, C5R1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P21730
#2: Protein C5a anaphylatoxin


Mass: 8288.676 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: C5 / Production host: Escherichia coli (E. coli) / References: UniProt: P01031

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

#3: 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
#4: 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
#5: 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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Antibody , 1 types, 1 molecules H

#6: 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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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
1C5a bound human C5aR1 in complex with GoCOMPLEXall0MULTIPLE SOURCES
2C5a anaphylatoxin chemotactic receptor 1COMPLEX#11RECOMBINANT
3C5a anaphylatoxinCOMPLEX#21RECOMBINANT
4Guanine nucleotide-binding protein G(o) subunit alphaCOMPLEX#31RECOMBINANT
5Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1COMPLEX#41RECOMBINANT
6Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2COMPLEX#51RECOMBINANT
7Antibody fragment - ScFv16COMPLEX#61RECOMBINANT
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
22Homo sapiens (human)9606
33Homo sapiens (human)9606
44Homo sapiens (human)9606
54Homo sapiens (human)9606
65Homo sapiens (human)9606
76Homo sapiens (human)9606
87Mus musculus (house mouse)10090
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
22Spodoptera frugiperda (fall armyworm)7108
33Escherichia coli (E. coli)562
47Escherichia coli (E. coli)562
54Escherichia coli (E. coli)562
65Spodoptera frugiperda (fall armyworm)7108
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: 10151
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: 10259948
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.21 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 292441 / Symmetry type: POINT
Atomic model buildingProtocol: FLEXIBLE FIT / Space: REAL
Atomic model buildingPDB-ID: 7WVV

7wvv


Accession code: 7WVV / Source name: PDB / Type: experimental model

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