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Basic information
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| Title | C5a bound C5aR1 in complex with beta-arrestin1 | |||||||||
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Keywords | C5aR2 / GPCR / membrane protein / active / arrestin / C5a-desArg / MEMBRANE PROTEIN/IMMUNE SYSTEM / MEMBRANE PROTEIN-IMMUNE SYSTEM complex | |||||||||
| Function / homology | Function and homology informationTGFBR3 regulates TGF-beta signaling / presynapse organization / complement component C5a signaling pathway / MAP2K and MAPK activation / Activation of SMO / Golgi Associated Vesicle Biogenesis / renal water retention / Defective AVP does not bind AVPR2 and causes neurohypophyseal diabetes insipidus (NDI) / Lysosome Vesicle Biogenesis / regulation of systemic arterial blood pressure by vasopressin ...TGFBR3 regulates TGF-beta signaling / presynapse organization / complement component C5a signaling pathway / MAP2K and MAPK activation / Activation of SMO / Golgi Associated Vesicle Biogenesis / renal water retention / Defective AVP does not bind AVPR2 and causes neurohypophyseal diabetes insipidus (NDI) / Lysosome Vesicle Biogenesis / regulation of systemic arterial blood pressure by vasopressin / Terminal pathway of complement / Vasopressin-like receptors / vasopressin receptor activity / membrane attack complex / renal water absorption / complement component C5a receptor activity / AP-2 adaptor complex binding / Ub-specific processing proteases / clathrin coat of coated pit / Cargo recognition for clathrin-mediated endocytosis / clathrin heavy chain binding / telencephalon development / hemostasis / Activation of C3 and C5 / Clathrin-mediated endocytosis / negative regulation of macrophage chemotaxis / sensory perception of chemical stimulus / complement activation, GZMK pathway / other organism cell membrane / clathrin-dependent endocytosis / desensitization of G protein-coupled receptor signaling pathway / acetylcholine receptor binding / complement receptor mediated signaling pathway / complement activation, alternative pathway / G protein-coupled receptor internalization / positive regulation of neutrophil chemotaxis / inositol hexakisphosphate binding / chemokine activity / Thrombin signalling through proteinase activated receptors (PARs) / G alpha (s) signalling events / clathrin binding / sensory perception / endopeptidase inhibitor activity / positive regulation of macrophage chemotaxis / small molecule binding / positive regulation of systemic arterial blood pressure / pseudopodium / phosphatidylinositol-3,4,5-trisphosphate binding / positive regulation of intracellular signal transduction / amyloid-beta clearance / negative regulation of Notch signaling pathway / positive regulation of receptor internalization / complement activation, classical pathway / positive regulation of vascular endothelial growth factor production / positive regulation of vasoconstriction / endocytic vesicle / cellular defense response / activation of adenylate cyclase activity / cellular response to hormone stimulus / positive regulation of chemokine production / response to cytokine / astrocyte activation / positive regulation of epithelial cell proliferation / Regulation of Complement cascade / secretory granule membrane / Peptide ligand-binding receptors / clathrin-coated endocytic vesicle membrane / microglial cell activation / receptor internalization / positive regulation of protein phosphorylation / mRNA transcription by RNA polymerase II / G protein-coupled receptor binding / cognition / chemotaxis / G protein-coupled receptor activity / positive regulation of angiogenesis / 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 / Vasopressin regulates renal water homeostasis via Aquaporins / Cargo recognition for clathrin-mediated endocytosis / protein transport / Clathrin-mediated endocytosis / positive regulation of cytosolic calcium ion concentration / adenylate cyclase-activating G protein-coupled receptor signaling pathway / cytoplasmic vesicle / killing of cells of another organism / G alpha (i) signalling events / molecular adaptor activity / G alpha (s) signalling events / basolateral plasma membrane / ubiquitin-dependent protein catabolic process / positive regulation of ERK1 and ERK2 cascade / cell surface receptor signaling pathway / endosome / immune response / inflammatory response / G protein-coupled receptor signaling pathway / negative regulation of cell population proliferation Similarity search - Function | |||||||||
| Biological species | Homo sapiens (human) / ![]() ![]() | |||||||||
| Method | single particle reconstruction / cryo EM / Resolution: 2.7 Å | |||||||||
Authors | Qin J / Cai C / Shan M / Zhang Y | |||||||||
| Funding support | 1 items
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Citation | Journal: Cell Res / Year: 2026Title: Atypical signaling, ligand recognition and selective agonist discovery of complement receptor C5aR2. Authors: Jiao Qin / Chenxi Cai / Mayu Shan / Suqing Zhou / Qingya Shen / Tianyi Zhu / Mingming Zhao / Yang Mei / Fanghan Ji / Dan-Dan Shen / Shao-Kun Zang / Huibing Zhang / Haomang Xu / Ming Yang / ...Authors: Jiao Qin / Chenxi Cai / Mayu Shan / Suqing Zhou / Qingya Shen / Tianyi Zhu / Mingming Zhao / Yang Mei / Fanghan Ji / Dan-Dan Shen / Shao-Kun Zang / Huibing Zhang / Haomang Xu / Ming Yang / Wei-Wei Wang / Rong Xiao / Bing Yang / Chunyou Mao / Zhenhua Shao / Haijing Wu / Qianjin Lu / Yan Zhang / ![]() Abstract: C5a, the most potent anaphylatoxin in the complement system, exerts its effects through the canonical G protein-coupled receptor C5aR1 and the arrestin-coupled receptor C5aR2. Despite the critical ...C5a, the most potent anaphylatoxin in the complement system, exerts its effects through the canonical G protein-coupled receptor C5aR1 and the arrestin-coupled receptor C5aR2. Despite the critical role of C5aR2 in immunomodulation, the molecular mechanisms underlying its biased signaling, ligand recognition, and associated pathophysiology remain poorly understood. Here, we report cryo-electron microscopy structures of β-arrestin 1-bound C5aR2 and C5aR1 stimulated by C5a or its metabolite C5a. By combining structural analysis with functional assays, we identified the key structural determinants that prevent G protein coupling and confer intrinsic bias toward β-arrestins. Comparative analysis elucidated the distinct ligand recognition mechanism of C5aR2 and explained the retained affinity of C5a for C5aR2. These findings guided the rational design of ZQ105, a highly selective C5aR2 agonist. Leveraging ZQ105 as a chemical probe, functional studies revealed that selective C5aR2 activation induces distinct pro-inflammatory responses and receptor internalization in neutrophils. This study provides novel structural insights into transducer engagement and ligand recognition by C5aR2, yielding a valuable pharmacological tool for exploring C5aR2-related pathophysiological processes. | |||||||||
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Structure visualization
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Downloads & links
-EMDB archive
| Header (meta data) | emd-68264-v30.xml emd-68264.xml | 17.4 KB 17.4 KB | Display Display | EMDB header |
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| Images | emd_68264.png | 45.1 KB | ||
| Map data | emd_68264.map.gz | 59.7 MB | EMDB map data format | |
| Filedesc metadata | emd-68264.cif.gz | 6.5 KB | ||
| Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-68264 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-68264 | HTTPS FTP |
-Related structure data
| Related structure data | ![]() 22gmMC ![]() 68177 ![]() 68262 ![]() 68263 ![]() 68516 ![]() 68517 ![]() 68520 ![]() 68524 ![]() 68525 ![]() 68529 ![]() 68531 ![]() 68534 ![]() 77405 ![]() 22crC ![]() 22gkC ![]() 22glC C: citing same article ( M: atomic model generated by this map |
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| Similar structure data | Similarity search - Function & homology F&H Search |
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Links
| EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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| Related items in Molecule of the Month |
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Map
-Supplemental data
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Sample components
-Entire : C5a anaphylatoxin chemotactic receptor 1
| Entire | Name: C5a anaphylatoxin chemotactic receptor 1 |
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| Components |
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-Supramolecule #1: C5a anaphylatoxin chemotactic receptor 1
| Supramolecule | Name: C5a anaphylatoxin chemotactic receptor 1 / type: organelle_or_cellular_component / ID: 1 / Parent: 0 / Macromolecule list: #2-#4 |
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| Source (natural) | Organism: Homo sapiens (human) |
-Macromolecule #1: C5a anaphylatoxin
| Macromolecule | Name: C5a anaphylatoxin / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO |
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| Source (natural) | Organism: Homo sapiens (human) |
| Molecular weight | Theoretical: 8.342727 KDa |
| Recombinant expression | Organism: ![]() |
| Sequence | String: TLQKKIEEIA AKYKHSVVKK CCYDGARVNN DETCEQRAAR ISLGPRCIKA FTECCVVASQ LRANISHKDM QLGR UniProtKB: Complement C5 |
-Macromolecule #2: C5a anaphylatoxin chemotactic receptor 1,Vasopressin V2 receptor
| Macromolecule | Name: C5a anaphylatoxin chemotactic receptor 1,Vasopressin V2 receptor type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO |
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| Source (natural) | Organism: Homo sapiens (human) |
| Molecular weight | Theoretical: 41.403648 KDa |
| Recombinant expression | Organism: ![]() |
| Sequence | String: 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 SVVRGGGSGG GSGGASARGR EPPELGPQDE (SEP)C(TPO)(TPO)A(SEP)(SEP)(SEP)LA KDTSS UniProtKB: C5a anaphylatoxin chemotactic receptor 1, Vasopressin V2 receptor |
-Macromolecule #3: Fab30 heavy chain
| Macromolecule | Name: Fab30 heavy chain / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO |
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| Source (natural) | Organism: ![]() |
| Molecular weight | Theoretical: 20.906475 KDa |
| Recombinant expression | Organism: ![]() |
| Sequence | String: VQLVESGGGL VQPGGSLRLS CAASGFNVYS SSIHWVRQAP GKGLEWVASI SSYYGYTYYA DSVKGRFTIS ADTSKNTAYL QMNSLRAED TAVYYCARSR QFWYSGLDYW GQGTLVTVSS ASTKGPSVFP LLGCLVKDYF PEPVTVSWNS GALGVHTFPA V LQSSGLYS ...String: VQLVESGGGL VQPGGSLRLS CAASGFNVYS SSIHWVRQAP GKGLEWVASI SSYYGYTYYA DSVKGRFTIS ADTSKNTAYL QMNSLRAED TAVYYCARSR QFWYSGLDYW GQGTLVTVSS ASTKGPSVFP LLGCLVKDYF PEPVTVSWNS GALGVHTFPA V LQSSGLYS LSSVVTVYIC NVNHKPSNTK VDKKV |
-Macromolecule #4: Fab30 light chain
| Macromolecule | Name: Fab30 light chain / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO |
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| Source (natural) | Organism: Homo sapiens (human) |
| Molecular weight | Theoretical: 17.692611 KDa |
| Recombinant expression | Organism: ![]() |
| Sequence | String: SDIQMTQSPS SLSASVGDRV TITCRASQSV SSAVAWYQQK PGKAPKLLIY SASSLYSGVP SRFSGSRSGT DFTLTISSLQ PEDFATYYC QQYKYVPVTF GQGTKVEIKR TVAAPSVFIF PPSDSQLKAS VVCLLNNPRQ SGNSQESVTE QDSKDSTYSL S STLT |
-Macromolecule #5: Beta-arrestin-1
| Macromolecule | Name: Beta-arrestin-1 / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO |
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| Source (natural) | Organism: ![]() |
| Molecular weight | Theoretical: 38.980805 KDa |
| Recombinant expression | Organism: ![]() |
| Sequence | String: TRVFKKASPN GKLTVYLGKR DFVDHIDLVE PVDGVVLVDP EYLKERRVYV TLTCAFRYGR EDLDVLGLTF RKDLFVANVQ SFPPAPEDK KPLTRLQERL IKKLGEHAYP FTFEIPPNLP CSVTLQPGPE DTGKACGVDY EVKAFCAENL EEKIHKRNSV R LVIEKVQY ...String: TRVFKKASPN GKLTVYLGKR DFVDHIDLVE PVDGVVLVDP EYLKERRVYV TLTCAFRYGR EDLDVLGLTF RKDLFVANVQ SFPPAPEDK KPLTRLQERL IKKLGEHAYP FTFEIPPNLP CSVTLQPGPE DTGKACGVDY EVKAFCAENL EEKIHKRNSV R LVIEKVQY APERPGPQPT AETTRQFLMS DKPLHLEASL DKEIYYHGEP ISVNVHVTNN TNKTVKKIKI SVRQYADICL FN TAQYKCP VAMEEADDTV APSSTFCKVY TLTPFLANNR EKRGLALDGK LKHEDTNLAS STLLREGANR EILGIIVSYK VKV KLVVSR GGLLGDLASS DVAVELPFTL M UniProtKB: Beta-arrestin-1 |
-Experimental details
-Structure determination
| Method | cryo EM |
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Processing | single particle reconstruction |
| Aggregation state | particle |
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Sample preparation
| Buffer | pH: 7.5 |
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| Vitrification | Cryogen name: ETHANE |
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Electron microscopy
| Microscope | TFS KRIOS |
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| Image recording | Film or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 52.0 e/Å2 |
| Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
| Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 1.5 µm / Nominal defocus min: 0.7000000000000001 µm |
| Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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Keywords
Homo sapiens (human)
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Processing
FIELD EMISSION GUN
