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- PDB-8hqc: Structure of a GPCR-G protein in complex with a natural peptide a... -

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Entry
Database: PDB / ID: 8hqc
TitleStructure of a GPCR-G protein in complex with a natural peptide agonist
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Antibody fragment
  • C5a anaphylatoxin
  • C5a anaphylatoxin chemotactic receptor 1
KeywordsSIGNALING PROTEIN/IMMUNE SYSTEM / GPCR / G protein / SIGNALING PROTEIN / SIGNALING PROTEIN-IMMUNE SYSTEM complex
Function / homology
Function and homology information


presynapse organization / Peptide ligand-binding receptors / complement component C5a receptor activity / Regulation of Complement cascade / Terminal pathway of complement / response to peptidoglycan / membrane attack complex / G alpha (i) signalling events / Activation of C3 and C5 / negative regulation of macrophage chemotaxis ...presynapse organization / Peptide ligand-binding receptors / complement component C5a receptor activity / Regulation of Complement cascade / Terminal pathway of complement / response to peptidoglycan / membrane attack complex / G alpha (i) signalling events / Activation of C3 and C5 / negative regulation of macrophage chemotaxis / mu-type opioid receptor binding / corticotropin-releasing hormone receptor 1 binding / complement activation, alternative pathway / vesicle docking involved in exocytosis / chemokine activity / positive regulation of neutrophil chemotaxis / G protein-coupled dopamine receptor signaling pathway / endopeptidase inhibitor activity / regulation of heart contraction / parallel fiber to Purkinje cell synapse / positive regulation of macrophage chemotaxis / amyloid-beta clearance / positive regulation of vascular endothelial growth factor production / complement activation, classical pathway / postsynaptic modulation of chemical synaptic transmission / negative regulation of insulin secretion / positive regulation of chemokine production / G protein-coupled serotonin receptor binding / adenylate cyclase regulator activity / adenylate cyclase-inhibiting serotonin receptor signaling pathway / muscle contraction / neutrophil chemotaxis / Neutrophil degranulation / Peptide ligand-binding receptors / positive regulation of epithelial cell proliferation / Regulation of Complement cascade / GABA-ergic synapse / locomotory behavior / astrocyte activation / microglial cell activation / mRNA transcription by RNA polymerase II / G protein-coupled receptor activity / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / G-protein beta/gamma-subunit complex binding / Olfactory Signaling Pathway / cognition / 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 / positive regulation of angiogenesis / 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 / chemotaxis / 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 / ADP signalling through P2Y purinoceptor 1 / G beta:gamma signalling through PI3Kgamma / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / adenylate cyclase-activating dopamine receptor signaling pathway / apical part of cell / 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) / presynaptic membrane / G protein activity / cell body / GTPase binding / Ca2+ pathway / retina development in camera-type eye / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / cytoplasmic vesicle / fibroblast proliferation / G alpha (i) signalling events / basolateral plasma membrane / Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement / G alpha (s) signalling events / phospholipase C-activating G protein-coupled receptor signaling pathway
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 / 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. / WD domain, G-beta repeat / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / 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 speciesMus musculus (house mouse)
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.89 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 1.1Jul 17, 2024Group: Data collection / Database references / Category: citation / citation_author / em_admin / Item: _em_admin.last_update
Revision 1.2Oct 30, 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

Downloads & links

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Assembly

Deposited unit
A: C5a anaphylatoxin chemotactic receptor 1
B: Guanine nucleotide-binding protein G(o) subunit alpha
C: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
D: C5a anaphylatoxin
G: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
H: Antibody fragment


Theoretical massNumber of molelcules
Total (without water)154,0086
Polymers154,0086
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: 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): "MGKTIIALSYIFCLVFADYKDDDDAANFTPVNGSSGNQSVRLVTSSSLEVLFQGPGSDPIDNSSFEINYDHYGTMDPNI" The residues ...Details: The initial sequence in the sample sequence is the expression tag (absent in the coordinates): "MGKTIIALSYIFCLVFADYKDDDDAANFTPVNGSSGNQSVRLVTSSSLEVLFQGPGSDPIDNSSFEINYDHYGTMDPNI" The residues absent in the coordinates and present in the sample sequence belongs to disordered regions.
Source: (gene. exp.) Mus musculus (house mouse) / Gene: C5ar1, C5ar, C5r1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P30993
#4: 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, CPAMD4 / Production host: Escherichia coli (E. coli) / References: UniProt: P01031

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

#2: 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 called the "mini G(o) alpha";Expression tag: "MGHHHHHHENLYFQGT" Residues absent in the coordinates: Disordered ...Details: This is a variant of Guanine nucleotide-binding protein G(o) subunit alpha called the "mini G(o) alpha";Expression tag: "MGHHHHHHENLYFQGT" Residues absent in the coordinates: Disordered regions,This is a variant of Guanine nucleotide-binding protein G(o) subunit alpha called the "mini G(o) alpha";Expression tag: "MGHHHHHHENLYFQGT" Residues absent in the coordinates: Disordered regions
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
Details: 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 / G gamma-I


Mass: 7861.143 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: Residues absent in the coordinates: Disordered regions
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


Mass: 27340.482 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: Residues absent in the coordinate file: Disordered regions
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-IDSourceDetails
1GPCR-G protein in complex with a natural peptide agonistCOMPLEXall0MULTIPLE SOURCES
2C5a anaphylatoxin chemotactic receptor 1COMPLEX#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
5C5a anaphylatoxinCOMPLEX#41RECOMBINANT
6Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2COMPLEX#51RECOMBINANT
7Antibody fragmentCOMPLEX#61RECOMBINANT
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
22Mus musculus (house mouse)10090
33Homo 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
54Spodoptera frugiperda (fall armyworm)7108
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

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: 1.19.2_4158: / Classification: refinement
EM software
IDNameVersionCategory
7Cootmodel fitting
9PHENIXmodel refinement
12cryoSPARC3.3.2classification
13cryoSPARC3.3.23D reconstruction
CTF correctionType: NONE
3D reconstructionResolution: 3.89 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 173416 / Symmetry type: POINT
Atomic model buildingProtocol: FLEXIBLE FIT / Space: REAL
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0038766
ELECTRON MICROSCOPYf_angle_d0.66311957
ELECTRON MICROSCOPYf_dihedral_angle_d4.9831256
ELECTRON MICROSCOPYf_chiral_restr0.0441431
ELECTRON MICROSCOPYf_plane_restr0.0051518

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