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- PDB-8hpt: Structure of C5a-pep bound mouse C5aR1 in complex with Go -

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Basic information

Entry
Database: PDB / ID: 8hpt
TitleStructure of C5a-pep bound mouse C5aR1 in complex with Go
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Antibody fragment ScFv16
  • C5a anaphylatoxin chemotactic receptor 1
  • MEA-LYS-PRO-ZAL-ALC-DAR
KeywordsSIGNATLING PROTEIN/IMMUNE SYSTEM / GPCR / G protein / SIGNALING PROTEIN / SIGNATLING PROTEIN-IMMUNE SYSTEM complex
Function / homology
Function and homology information


complement component C5a binding / cell proliferation in hindbrain / presynapse organization / regulation of tau-protein kinase activity / complement component C5a receptor activity / Peptide ligand-binding receptors / Regulation of Complement cascade / response to peptidoglycan / G alpha (i) signalling events / mu-type opioid receptor binding ...complement component C5a binding / cell proliferation in hindbrain / presynapse organization / regulation of tau-protein kinase activity / complement component C5a receptor activity / Peptide ligand-binding receptors / Regulation of Complement cascade / response to peptidoglycan / G alpha (i) signalling events / mu-type opioid receptor binding / complement receptor mediated signaling pathway / corticotropin-releasing hormone receptor 1 binding / vesicle docking involved in exocytosis / positive regulation of neutrophil chemotaxis / G protein-coupled dopamine receptor signaling pathway / regulation of heart contraction / positive regulation of macrophage chemotaxis / amyloid-beta clearance / positive regulation of vascular endothelial growth factor production / negative regulation of insulin secretion / G protein-coupled serotonin receptor binding / muscle contraction / neutrophil chemotaxis / Neutrophil degranulation / positive regulation of epithelial cell proliferation / 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 / Activation of the phototransduction cascade / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / 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 / positive regulation of angiogenesis / cellular response to catecholamine stimulus / ADORA2B mediated anti-inflammatory cytokines production / sensory perception of taste / 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 / extracellular vesicle / signaling receptor complex adaptor activity / apical part of cell / Thrombin signalling through proteinase activated receptors (PARs) / 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 / cytoplasmic vesicle / Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement / G alpha (s) signalling events / basolateral plasma membrane / G alpha (q) signalling events / negative regulation of neuron apoptotic process / Ras protein signal transduction / cell population proliferation / Extra-nuclear estrogen signaling / positive regulation of ERK1 and ERK2 cascade / defense response to Gram-positive bacterium / inflammatory response / G protein-coupled receptor signaling pathway / lysosomal membrane / GTPase activity / dendrite / synapse / protein-containing complex binding / GTP binding
Similarity search - Function
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. ...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 / 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 speciesMus musculus (house mouse)
Homo sapiens (human)
synthetic construct (others)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.39 Å
AuthorsSaha, S. / Maharana, J. / Yadav, M.K. / Sarma, P. / Chami, M. / Banerjee, R. / Shukla, A.K.
Funding support India, 1items
OrganizationGrant numberCountry
Department of Biotechnology (DBT, India)BT/PR29041/BRB/10/1697/20 India
Citation
Journal: 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.
#1: Journal: Cell(Cambridge,Mass.) / Year: 2023
Title: Structure of a GPCR-G protein in complex with a synthetic peptide agonist
Authors: Saha, S. / Maharana, J. / Yadav, M.K. / Sarma, P. / Chami, M. / Banerjee, R. / Shukla, A.K.
History
DepositionDec 13, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Oct 18, 2023Provider: repository / Type: Initial release
Revision 1.1Nov 15, 2023Group: Data collection / Category: chem_comp_atom / chem_comp_bond / Item: _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_2
Revision 1.2Jul 17, 2024Group: Data collection / Database references / Category: citation / citation_author / em_admin / Item: _em_admin.last_update

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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: MEA-LYS-PRO-ZAL-ALC-DAR
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)143,5526
Polymers143,5526
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 BCG

#3: Protein Guanine nucleotide-binding protein G(o) subunit alpha


Mass: 27024.762 Da / Num. of mol.: 1 / Mutation: G42D,E43N,A227D,G230D,I332A,V335I
Source method: isolated from a genetically manipulated source
Details: This is a variant of Guanine nucleotide-binding protein G(o) subunit alpha (Uniprot ID: P09471) called the "mini G(o) alpha";The initial sequence in the provided sample sequence is the ...Details: This is a variant of Guanine nucleotide-binding protein G(o) subunit alpha (Uniprot ID: P09471) called the "mini G(o) alpha";The initial sequence in the provided sample sequence is the expression tag: "MGHHHHHHENLYFQGT",This is a variant of Guanine nucleotide-binding protein G(o) subunit alpha (Uniprot ID: P09471) called the "mini G(o) alpha";The initial sequence in the provided sample sequence is the expression tag: "MGHHHHHHENLYFQGT"
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


Mass: 37198.656 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: The initial sequence present in the sample sequence and absent in the coordinates is the expression tag: "MHHHHHHGSSGS"
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


Mass: 6160.126 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: The missing residues in the coordinates are the regions which are disordered.
Source: (gene. exp.) Homo sapiens (human) / Gene: GNG2 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P59768

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Protein / Protein/peptide / Antibody , 3 types, 3 molecules ADH

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


Mass: 44958.422 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: The initial sequence in the sample sequence is the expression tag (absent in the coordinates): "MGKTIIALSYIFCLVFADYKDDDDAANFTPVNGSSGNQSVRLVTSSSLEVLFQGPGSDPIDNSSFEINYDHYGTMDPNIPADGIHLPKRQP" ...Details: The initial sequence in the sample sequence is the expression tag (absent in the coordinates): "MGKTIIALSYIFCLVFADYKDDDDAANFTPVNGSSGNQSVRLVTSSSLEVLFQGPGSDPIDNSSFEINYDHYGTMDPNIPADGIHLPKRQP" The residues missing in the coordinates as compared to the sample sequence are the residues with disorder.
Source: (gene. exp.) Mus musculus (house mouse) / Gene: C5ar1, C5ar, C5r1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P30993
#2: Protein/peptide MEA-LYS-PRO-ZAL-ALC-DAR


Mass: 869.148 Da / Num. of mol.: 1 / Source method: obtained synthetically
Details: This is a chemically synthesized peptide derived from the C-terminus of human C5a.
Source: (synth.) synthetic construct (others)
#6: Antibody Antibody fragment ScFv16


Mass: 27340.482 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: The residues absent in the coordinates are the regions which are disordered.
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Escherichia coli (E. coli)

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Details

Has ligand of interestY

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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
1GPCR-G protein in complex with a synthetic peptide agonistCOMPLEXall0MULTIPLE SOURCES
2C5a anaphylatoxin chemotactic receptor 1COMPLEX#11RECOMBINANT
3synthetic peptideCOMPLEX#21RECOMBINANTChemically synthesized peptide fragment derived from the C-terminus of human C5a.
4Guanine nucleotide-binding protein G(o) subunit alphaCOMPLEX#31RECOMBINANTThis is a variant of Guanine nucleotide-binding protein G(o) subunit alpha (Uniprot ID: P09471) called the "mini G(o) alpha"
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 fragmentCOMPLEX#61RECOMBINANTSingle Chain Variable Fragment of an antibody referred to as ScFv16
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
22Mus musculus (house mouse)10090
34Homo sapiens (human)9606
47Mus musculus (house mouse)9606
55Homo sapiens (human)9606
66Homo sapiens (human)9606
77Mus musculus (house mouse)10090
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
22Spodoptera frugiperda (fall armyworm)7108
34Escherichia coli (E. coli)562
47Escherichia coli (E. coli)562
55Spodoptera frugiperda (fall armyworm)7108
66Spodoptera frugiperda (fall armyworm)7108
77Escherichia 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

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2500 nm / Nominal defocus min: 500 nm
Image recordingElectron dose: 42 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 SUMMIT (4k x 4k)
Image scansMovie frames/image: 40

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Processing

SoftwareName: PHENIX / Version: 1.20.1_4487: / Classification: refinement
EM software
IDNameVersionCategory
7Cootmodel fitting
9PHENIXmodel refinement
12cryoSPARC3.3.2classification
13cryoSPARC3.3.23D reconstruction
CTF correctionType: NONE
3D reconstructionResolution: 3.39 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 380463 / Symmetry type: POINT
Atomic model buildingProtocol: FLEXIBLE FIT / Space: REAL
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0058064
ELECTRON MICROSCOPYf_angle_d0.6811011
ELECTRON MICROSCOPYf_dihedral_angle_d5.341169
ELECTRON MICROSCOPYf_chiral_restr0.0421307
ELECTRON MICROSCOPYf_plane_restr0.0081398

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