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- EMDB-33634: Cryo-EM structure of C5a peptide-bound C5aR1 in complex with Gi p... -

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Entry
Database: EMDB / ID: EMD-33634
TitleCryo-EM structure of C5a peptide-bound C5aR1 in complex with Gi protein
Map data
Sample
  • Complex: C5apep-bound C5aR1 in complex with Gi heterotrimer
    • Complex: Gi heterotrimer
      • Protein or peptide: Guanine nucleotide-binding protein G(i) subunit alpha-1
      • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
      • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
    • Complex: C5apep-bound C5aR1
      • Protein or peptide: C5apep peptide
      • Protein or peptide: C5a anaphylatoxin chemotactic receptor 1
    • Complex: scFV16
      • Protein or peptide: scFV16
Function / homology
Function and homology information


presynapse organization / complement component C5a signaling pathway / complement component C5a receptor activity / sensory perception of chemical stimulus / complement receptor mediated signaling pathway / positive regulation of neutrophil chemotaxis / positive regulation of macrophage chemotaxis / amyloid-beta clearance / positive regulation of vascular endothelial growth factor production / cellular defense response ...presynapse organization / complement component C5a signaling pathway / complement component C5a receptor activity / sensory perception of chemical stimulus / complement receptor mediated signaling pathway / positive regulation of neutrophil chemotaxis / positive regulation of macrophage chemotaxis / amyloid-beta clearance / positive regulation of vascular endothelial growth factor production / cellular defense response / regulation of eating behavior / adenylate cyclase inhibitor activity / T cell migration / positive regulation of protein localization to cell cortex / positive regulation of relaxation of smooth muscle / Adenylate cyclase inhibitory pathway / astrocyte activation / D2 dopamine receptor binding / positive regulation of epithelial cell proliferation / adenylate cyclase-inhibiting serotonin receptor signaling pathway / G protein-coupled serotonin receptor binding / Regulation of Complement cascade / secretory granule membrane / cellular response to forskolin / Peptide ligand-binding receptors / regulation of mitotic spindle organization / mast cell degranulation / chemokine-mediated signaling pathway / neuropeptide signaling pathway / Regulation of insulin secretion / microglial cell activation / response to prostaglandin E / positive regulation of cholesterol biosynthetic process / mRNA transcription by RNA polymerase II / G protein-coupled receptor binding / cognition / response to peptide hormone / chemotaxis / G protein-coupled receptor activity / positive regulation of angiogenesis / G-protein beta/gamma-subunit complex binding / apical part of cell / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / phospholipase C-activating G protein-coupled receptor signaling pathway / Olfactory Signaling Pathway / Activation of the phototransduction cascade / G protein-coupled acetylcholine receptor signaling pathway / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G-protein activation / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / Prostacyclin signalling through prostacyclin receptor / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / GDP binding / G beta:gamma signalling through BTK / photoreceptor disc membrane / ADP signalling through P2Y purinoceptor 12 / Glucagon-type ligand receptors / Sensory perception of sweet, bitter, and umami (glutamate) taste / Adrenaline,noradrenaline inhibits insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / G alpha (z) signalling events / cellular response to catecholamine stimulus / ADP signalling through P2Y purinoceptor 1 / G beta:gamma signalling through PI3Kgamma / ADORA2B mediated anti-inflammatory cytokines production / adenylate cyclase-activating dopamine receptor signaling pathway / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / cellular response to prostaglandin E stimulus / GPER1 signaling / heterotrimeric G-protein complex / Inactivation, recovery and regulation of the phototransduction cascade / G alpha (12/13) signalling events / G-protein beta-subunit binding / extracellular vesicle / positive regulation of cytosolic calcium ion concentration / Thrombin signalling through proteinase activated receptors (PARs) / signaling receptor complex adaptor activity / adenylate cyclase-activating G protein-coupled receptor signaling pathway / GTPase binding / G protein activity / midbody / Ca2+ pathway / cell cortex / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / G alpha (i) signalling events / G alpha (s) signalling events / basolateral plasma membrane / G alpha (q) signalling events / Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement / ciliary basal body / Ras protein signal transduction / positive regulation of ERK1 and ERK2 cascade / Extra-nuclear estrogen signaling
Similarity search - Function
Anaphylatoxin chemotactic receptor, C3a/C5a1/C5a2 / Formyl peptide receptor-related / G-protein alpha subunit, group I / G protein alpha subunit, helical insertion / G protein alpha subunit / Guanine nucleotide binding protein (G-protein), alpha subunit / G-protein alpha subunit / G-alpha domain profile. / 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 / G protein alpha subunit, helical insertion / G protein alpha subunit / Guanine nucleotide binding protein (G-protein), alpha subunit / G-protein alpha subunit / G-alpha domain profile. / 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 / G protein beta WD-40 repeat protein / Guanine nucleotide-binding protein, beta subunit / G-protein, beta subunit / G-protein coupled receptors family 1 signature. / 7 transmembrane receptor (rhodopsin family) / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. / 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. / 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
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 / Guanine nucleotide-binding protein G(i) subunit alpha-1
Similarity search - Component
Biological speciesHomo sapiens (human) / Mus musculus (house mouse) / synthetic construct (others)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsFeng YY / Zhao C / Yan W / Shao ZH
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)31972916 China
CitationJournal: Cell Res / Year: 2023
Title: Mechanism of activation and biased signaling in complement receptor C5aR1.
Authors: Yuying Feng / Chang Zhao / Yue Deng / Heli Wang / Liang Ma / Sicen Liu / Xiaowen Tian / Bo Wang / Yan Bin / Peipei Chen / Wei Yan / Ping Fu / Zhenhua Shao /
Abstract: The complement system plays an important role in the innate immune response to invading pathogens. The complement fragment C5a is one of its important effector components and exerts diverse ...The complement system plays an important role in the innate immune response to invading pathogens. The complement fragment C5a is one of its important effector components and exerts diverse physiological functions through activation of the C5a receptor 1 (C5aR1) and associated downstream G protein and β-arrestin signaling pathways. Dysfunction of the C5a-C5aR1 axis is linked to numerous inflammatory and immune-mediated diseases, but the structural basis for activation and biased signaling of C5aR1 remains elusive. Here, we present cryo-electron microscopy structures of the activated wild-type C5aR1-G protein complex bound to each of the following: C5a, the hexapeptidic agonist C5a, and the G protein-biased agonist BM213. The structures reveal the landscape of the C5a-C5aR1 interaction as well as a common motif for the recognition of diverse orthosteric ligands. Moreover, combined with mutagenesis studies and cell-based pharmacological assays, we deciphered a framework for biased signaling using different peptide analogs and provided insight into the activation mechanism of C5aR1 by solving the structure of C5aR1 mutant-G signaling activation complex induced by C089, which exerts antagonism on wild-type C5aR1. In addition, unusual conformational changes in the intracellular end of transmembrane domain 7 and helix 8 upon agonist binding suggest a differential signal transduction process. Collectively, our study provides mechanistic understanding into the ligand recognition, biased signaling modulation, activation, and G protein coupling of C5aR1, which may facilitate the future design of therapeutic agents.
History
DepositionJun 18, 2022-
Header (metadata) releaseMar 1, 2023-
Map releaseMar 1, 2023-
UpdateApr 19, 2023-
Current statusApr 19, 2023Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_33634.png

Downloads & links

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Map

FileDownload / File: emd_33634.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.85 Å/pix.
x 256 pix.
= 217.6 Å		0.85 Å/pix.
x 256 pix.
= 217.6 Å		0.85 Å/pix.
x 256 pix.
= 217.6 Å

Surface

Projections

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.85 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.264
Minimum - Maximum-1.1690828 - 2.0751104
Average (Standard dev.)0.0013873338 (±0.047239985)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 217.6 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_33634_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_33634_half_map_2.map
Projections & Slices
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Histogram (log scale)

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Sample components

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Entire : C5apep-bound C5aR1 in complex with Gi heterotrimer

EntireName: C5apep-bound C5aR1 in complex with Gi heterotrimer
Components
  • Complex: C5apep-bound C5aR1 in complex with Gi heterotrimer
    • Complex: Gi heterotrimer
      • Protein or peptide: Guanine nucleotide-binding protein G(i) subunit alpha-1
      • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
      • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
    • Complex: C5apep-bound C5aR1
      • Protein or peptide: C5apep peptide
      • Protein or peptide: C5a anaphylatoxin chemotactic receptor 1
    • Complex: scFV16
      • Protein or peptide: scFV16

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Supramolecule #1: C5apep-bound C5aR1 in complex with Gi heterotrimer

SupramoleculeName: C5apep-bound C5aR1 in complex with Gi heterotrimer / type: complex / ID: 1 / Chimera: Yes / Parent: 0 / Macromolecule list: all

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Supramolecule #2: Gi heterotrimer

SupramoleculeName: Gi heterotrimer / type: complex / ID: 2 / Chimera: Yes / Parent: 1 / Macromolecule list: #1-#3
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #3: C5apep-bound C5aR1

SupramoleculeName: C5apep-bound C5aR1 / type: complex / ID: 3 / Chimera: Yes / Parent: 1 / Macromolecule list: #4, #6
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #4: scFV16

SupramoleculeName: scFV16 / type: complex / ID: 4 / Chimera: Yes / Parent: 1 / Macromolecule list: #5
Source (natural)Organism: Mus musculus (house mouse)

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Macromolecule #1: Guanine nucleotide-binding protein G(i) subunit alpha-1

MacromoleculeName: Guanine nucleotide-binding protein G(i) subunit alpha-1
type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 40.415031 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MGCTLSAEDK AAVERSKMID RNLREDGEKA AREVKLLLLG AGESGKSTIV KQMKIIHEAG YSEEECKQYK AVVYSNTIQS IIAIIRAMG RLKIDFGDSA RADDARQLFV LAGAAEEGFM TAELAGVIKR LWKDSGVQAC FNRSREYQLN DSAAYYLNDL D RIAQPNYI ...String:
MGCTLSAEDK AAVERSKMID RNLREDGEKA AREVKLLLLG AGESGKSTIV KQMKIIHEAG YSEEECKQYK AVVYSNTIQS IIAIIRAMG RLKIDFGDSA RADDARQLFV LAGAAEEGFM TAELAGVIKR LWKDSGVQAC FNRSREYQLN DSAAYYLNDL D RIAQPNYI PTQQDVLRTR VKTTGIVETH FTFKDLHFKM FDVGGQRSER KKWIHCFEGV TAIIFCVALS DYDLVLAEDE EM NRMHESM KLFDSICNNK WFTDTSIILF LNKKDLFEEK IKKSPLTICY PEYAGSNTYE EAAAYIQCQF EDLNKRKDTK EIY THFTCA TDTKNVQFVF DAVTDVIIKN NLKDCGLF

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Macromolecule #2: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1

MacromoleculeName: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 39.141793 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MHHHHLEVLF QGPGSSGSEL DQLRQEAEQL KNQIRDARKA CADATLSQIT NNIDPVGRIQ MRTRRTLRGH LAKIYAMHWG TDSRLLVSA SQDGKLIIWD SYTTNKVHAI PLRSSWVMTC AYAPSGNYVA CGGLDNICSI YNLKTREGNV RVSRELAGHT G YLSCCRFL ...String:
MHHHHLEVLF QGPGSSGSEL DQLRQEAEQL KNQIRDARKA CADATLSQIT NNIDPVGRIQ MRTRRTLRGH LAKIYAMHWG TDSRLLVSA SQDGKLIIWD SYTTNKVHAI PLRSSWVMTC AYAPSGNYVA CGGLDNICSI YNLKTREGNV RVSRELAGHT G YLSCCRFL DDNQIVTSSG DTTCALWDIE TGQQTTTFTG HTGDVMSLSL APDTRLFVSG ACDASAKLWD VREGMCRQTF TG HESDINA ICFFPNGNAF ATGSDDATCR LFDLRADQEL MTYSHDNIIC GITSVSFSKS GRLLLAGYDD FNCNVWDALK ADR AGVLAG HDNRVSCLGV TDDGMAVATG SWDSFLKIWN

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Macromolecule #3: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2

MacromoleculeName: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 7.861143 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString:
MASNNTASIA QARKLVEQLK MEANIDRIKV SKAAADLMAY CEAHAKEDPL LTPVPASENP FREKKFFCAI L

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Macromolecule #4: C5apep peptide

MacromoleculeName: C5apep peptide / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: synthetic construct (others)
Molecular weightTheoretical: 869.148 Da
SequenceString:
(MEA)KP(ZAL)(ALC)(DAR)

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Macromolecule #5: scFV16

MacromoleculeName: scFV16 / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 28.767984 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MDVQLVESGG GLVQPGGSRK LSCSASGFAF SSFGMHWVRQ APEKGLEWVA YISSGSGTIY YADTVKGRFT ISRDDPKNTL FLQMTSLRS EDTAMYYCVR SIYYYGSSPF DFWGQGTTLT VSSGGGGSGG GGSGGGGSDI VMTQATSSVP VTPGESVSIS C RSSKSLLH ...String:
MDVQLVESGG GLVQPGGSRK LSCSASGFAF SSFGMHWVRQ APEKGLEWVA YISSGSGTIY YADTVKGRFT ISRDDPKNTL FLQMTSLRS EDTAMYYCVR SIYYYGSSPF DFWGQGTTLT VSSGGGGSGG GGSGGGGSDI VMTQATSSVP VTPGESVSIS C RSSKSLLH SNGNTYLYWF LQRPGQSPQL LIYRMSNLAS GVPDRFSGSG SGTAFTLTIS RLEAEDVGVY YCMQHLEYPL TF GAGTKLE LKAAAENLYF QGHHHHHHHH

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Macromolecule #6: C5a anaphylatoxin chemotactic receptor 1

MacromoleculeName: C5a anaphylatoxin chemotactic receptor 1 / type: protein_or_peptide / ID: 6 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 38.415238 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MDSFNYTTPD YGHYDDKDTL DLNTPVDKTS NTLRVPDILA LVIFAVVFLV GVLGNALVVW VTAFEAKRTI NAIWFLNLAV ADFLSCLAL PILFTSIVQH HHWPFGGAAC SILPSLILLN MYASILLLAT ISADRFLLVF KPIWCQNFRG AGLAWIACAV A WGLALLLT ...String:
MDSFNYTTPD YGHYDDKDTL DLNTPVDKTS NTLRVPDILA LVIFAVVFLV GVLGNALVVW VTAFEAKRTI NAIWFLNLAV ADFLSCLAL PILFTSIVQH HHWPFGGAAC SILPSLILLN MYASILLLAT ISADRFLLVF KPIWCQNFRG AGLAWIACAV A WGLALLLT IPSFLYRVVR EEYFPPKVLC GVDYSHDKRR ERAVAIVRLV LGFLWPLLTL TICYTFILLR TWSRRATRST KT LKVVVAV VASFFIFWLP YQVTGIMMSF LEPSSPTFLL LKKLDSLCVS FAYINCCINP IIYVVAGQGF QGRLRKSLPS LLR NVLTEE SVVRHHHHHH HHH

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Average electron dose: 62.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 4329433
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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