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Yorodumi- EMDB-33634: Cryo-EM structure of C5a peptide-bound C5aR1 in complex with Gi p... -
+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-33634 | |||||||||
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Title | Cryo-EM structure of C5a peptide-bound C5aR1 in complex with Gi protein | |||||||||
Map data | ||||||||||
Sample |
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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 / sensory perception of chemical stimulus / complement receptor mediated signaling pathway / positive regulation of neutrophil chemotaxis / positive regulation of macrophage chemotaxis / amyloid-beta clearance ...complement component C5a signaling pathway / presynapse organization / regulation of tau-protein kinase activity / complement component C5a receptor activity / response to peptidoglycan / 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 / T cell migration / D2 dopamine receptor binding / Adenylate cyclase inhibitory pathway / positive regulation of protein localization to cell cortex / cellular defense response / regulation of cAMP-mediated signaling / G protein-coupled serotonin receptor binding / cellular response to forskolin / regulation of mitotic spindle organization / neutrophil chemotaxis / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / G-protein beta/gamma-subunit complex binding / Peptide ligand-binding receptors / positive regulation of epithelial cell proliferation / secretory granule membrane / cognition / Regulation of Complement cascade / Regulation of insulin secretion / G protein-coupled receptor binding / G protein-coupled receptor activity / astrocyte activation / microglial cell activation / mRNA transcription by RNA polymerase II / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / Olfactory Signaling Pathway / Activation of the phototransduction cascade / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / Glucagon signaling in metabolic regulation / 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 / G beta:gamma signalling through CDC42 / response to peptide hormone / Vasopressin regulates renal water homeostasis via Aquaporins / G beta:gamma signalling through BTK / ADP signalling through P2Y purinoceptor 12 / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / Glucagon-type ligand receptors / Sensory perception of sweet, bitter, and umami (glutamate) taste / photoreceptor disc membrane / G alpha (z) signalling events / Adrenaline,noradrenaline inhibits insulin secretion / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / cellular response to catecholamine stimulus / sensory perception of taste / positive regulation of angiogenesis / ADP signalling through P2Y purinoceptor 1 / adenylate cyclase-activating dopamine receptor signaling pathway / G beta:gamma signalling through PI3Kgamma / GPER1 signaling / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / chemotaxis / GDP binding / 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 / Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement / Thrombin signalling through proteinase activated receptors (PARs) / apical part of cell / GTPase binding / retina development in camera-type eye / Ca2+ pathway / cell cortex / phospholipase C-activating G protein-coupled receptor signaling pathway / positive regulation of cytosolic calcium ion concentration / G alpha (i) signalling events / midbody / fibroblast proliferation / G alpha (s) signalling events / basolateral plasma membrane / G alpha (q) signalling events / 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 / immune response / G protein-coupled receptor signaling pathway / lysosomal membrane Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) / Mus musculus (house mouse) / synthetic construct (others) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.2 Å | |||||||||
Authors | Feng YY / Zhao C / Yan W / Shao ZH | |||||||||
Funding support | China, 1 items
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Citation | Journal: 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 |
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-Structure visualization
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_33634.map.gz | 59.7 MB | EMDB map data format | |
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Header (meta data) | emd-33634-v30.xml emd-33634.xml | 21 KB 21 KB | Display Display | EMDB header |
Images | emd_33634.png | 35.4 KB | ||
Others | emd_33634_half_map_1.map.gz emd_33634_half_map_2.map.gz | 59.2 MB 59.1 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-33634 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-33634 | HTTPS FTP |
-Validation report
Summary document | emd_33634_validation.pdf.gz | 890.5 KB | Display | EMDB validaton report |
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Full document | emd_33634_full_validation.pdf.gz | 890 KB | Display | |
Data in XML | emd_33634_validation.xml.gz | 12.3 KB | Display | |
Data in CIF | emd_33634_validation.cif.gz | 14.3 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-33634 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-33634 | HTTPS FTP |
-Related structure data
Related structure data | 7y65MC 7y64C 7y66C 7y67C M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_33634.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||
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Projections & slices | Image control
Images are generated by Spider. | ||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 0.85 Å | ||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Half map: #1
File | emd_33634_half_map_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #2
File | emd_33634_half_map_2.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Sample components
+Entire : C5apep-bound C5aR1 in complex with Gi heterotrimer
+Supramolecule #1: C5apep-bound C5aR1 in complex with Gi heterotrimer
+Supramolecule #2: Gi heterotrimer
+Supramolecule #3: C5apep-bound C5aR1
+Supramolecule #4: scFV16
+Macromolecule #1: Guanine nucleotide-binding protein G(i) subunit alpha-1
+Macromolecule #2: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
+Macromolecule #3: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
+Macromolecule #4: C5apep peptide
+Macromolecule #5: scFV16
+Macromolecule #6: C5a anaphylatoxin chemotactic receptor 1
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Buffer | pH: 7.5 |
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Vitrification | Cryogen name: ETHANE |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Average electron dose: 62.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination 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 |
-Image processing
Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 4329433 |
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Initial angle assignment | Type: MAXIMUM LIKELIHOOD |
Final angle assignment | Type: MAXIMUM LIKELIHOOD |