+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-41829 | |||||||||
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Title | Structure of a class A GPCR/agonist complex | |||||||||
Map data | ||||||||||
Sample |
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Keywords | GPCR / agonist / STRUCTURAL PROTEIN | |||||||||
Function / homology | Function and homology information chemokine receptor activity / CCR chemokine receptor binding / C-C chemokine receptor activity / C-C chemokine binding / eosinophil chemotaxis / positive regulation of monocyte chemotaxis / chemokine-mediated signaling pathway / Chemokine receptors bind chemokines / chemokine activity / positive regulation of interleukin-17 production ...chemokine receptor activity / CCR chemokine receptor binding / C-C chemokine receptor activity / C-C chemokine binding / eosinophil chemotaxis / positive regulation of monocyte chemotaxis / chemokine-mediated signaling pathway / Chemokine receptors bind chemokines / chemokine activity / positive regulation of interleukin-17 production / bioluminescence / Adenylate cyclase inhibitory pathway / positive regulation of protein localization to cell cortex / generation of precursor metabolites and energy / regulation of cAMP-mediated signaling / D2 dopamine receptor binding / G protein-coupled serotonin receptor binding / coreceptor activity / regulation of mitotic spindle organization / cellular response to forskolin / viral process / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / cell chemotaxis / Regulation of insulin secretion / G protein-coupled receptor binding / calcium-mediated signaling / 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 / response to peptide hormone / ADP signalling through P2Y purinoceptor 12 / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / Sensory perception of sweet, bitter, and umami (glutamate) taste / photoreceptor disc membrane / Adrenaline,noradrenaline inhibits insulin secretion / Glucagon-type ligand receptors / Vasopressin regulates renal water homeostasis via Aquaporins / intracellular calcium ion homeostasis / G alpha (z) signalling events / positive regulation of inflammatory response / cellular response to catecholamine stimulus / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / sensory perception of taste / ADP signalling through P2Y purinoceptor 1 / adenylate cyclase-activating dopamine receptor signaling pathway / G beta:gamma signalling through PI3Kgamma / cellular response to prostaglandin E stimulus / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / GPER1 signaling / GDP binding / chemotaxis / G-protein beta-subunit binding / Inactivation, recovery and regulation of the phototransduction cascade / heterotrimeric G-protein complex / antimicrobial humoral immune response mediated by antimicrobial peptide / G alpha (12/13) signalling events / extracellular vesicle / signaling receptor complex adaptor activity / 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 cortex / midbody / G alpha (i) signalling events / fibroblast proliferation / G alpha (s) signalling events / G alpha (q) signalling events / Ras protein signal transduction / Extra-nuclear estrogen signaling / cell population proliferation / cell adhesion / positive regulation of cell migration / inflammatory response / immune response / G protein-coupled receptor signaling pathway / cell division / external side of plasma membrane / lysosomal membrane / GTPase activity / centrosome / synapse / protein-containing complex binding / nucleolus / GTP binding Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) / Human adenovirus C serotype 2 / Mus musculus (house mouse) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.1 Å | |||||||||
Authors | Sun D / Johnson M / Masureel M | |||||||||
Funding support | 1 items
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Citation | Journal: Nat Commun / Year: 2023 Title: Structural basis of antibody inhibition and chemokine activation of the human CC chemokine receptor 8. Authors: Dawei Sun / Yonglian Sun / Eric Janezic / Tricia Zhou / Matthew Johnson / Caleigh Azumaya / Sigrid Noreng / Cecilia Chiu / Akiko Seki / Teresita L Arenzana / John M Nicoludis / Yongchang Shi ...Authors: Dawei Sun / Yonglian Sun / Eric Janezic / Tricia Zhou / Matthew Johnson / Caleigh Azumaya / Sigrid Noreng / Cecilia Chiu / Akiko Seki / Teresita L Arenzana / John M Nicoludis / Yongchang Shi / Baomei Wang / Hoangdung Ho / Prajakta Joshi / Christine Tam / Jian Payandeh / Laëtitia Comps-Agrar / Jianyong Wang / Sascha Rutz / James T Koerber / Matthieu Masureel / Abstract: The C-C motif chemokine receptor 8 (CCR8) is a class A G-protein coupled receptor that has emerged as a promising therapeutic target in cancer. Targeting CCR8 with an antibody has appeared to be an ...The C-C motif chemokine receptor 8 (CCR8) is a class A G-protein coupled receptor that has emerged as a promising therapeutic target in cancer. Targeting CCR8 with an antibody has appeared to be an attractive therapeutic approach, but the molecular basis for chemokine-mediated activation and antibody-mediated inhibition of CCR8 are not fully elucidated. Here, we obtain an antagonist antibody against human CCR8 and determine structures of CCR8 in complex with either the antibody or the endogenous agonist ligand CCL1. Our studies reveal characteristic antibody features allowing recognition of the CCR8 extracellular loops and CCL1-CCR8 interaction modes that are distinct from other chemokine receptor - ligand pairs. Informed by these structural insights, we demonstrate that CCL1 follows a two-step, two-site binding sequence to CCR8 and that antibody-mediated inhibition of CCL1 signaling can occur by preventing the second binding event. Together, our results provide a detailed structural and mechanistic framework of CCR8 activation and inhibition that expands our molecular understanding of chemokine - receptor interactions and offers insight into the development of therapeutic antibodies targeting chemokine GPCRs. | |||||||||
History |
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-Structure visualization
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_41829.map.gz | 43.5 MB | EMDB map data format | |
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Header (meta data) | emd-41829-v30.xml emd-41829.xml | 17.2 KB 17.2 KB | Display Display | EMDB header |
Images | emd_41829.png | 76.7 KB | ||
Filedesc metadata | emd-41829.cif.gz | 6.9 KB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-41829 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-41829 | HTTPS FTP |
-Validation report
Summary document | emd_41829_validation.pdf.gz | 478.2 KB | Display | EMDB validaton report |
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Full document | emd_41829_full_validation.pdf.gz | 477.8 KB | Display | |
Data in XML | emd_41829_validation.xml.gz | 6.6 KB | Display | |
Data in CIF | emd_41829_validation.cif.gz | 7.6 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-41829 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-41829 | HTTPS FTP |
-Related structure data
Related structure data | 8u1uMC 8tlmC C: citing same article (ref.) M: atomic model generated by this map |
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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_41829.map.gz / Format: CCP4 / Size: 91.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||
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Voxel size | X=Y=Z: 1.0153 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Sample components
-Entire : CCR8 in complex with CCL1 and Gi
Entire | Name: CCR8 in complex with CCL1 and Gi |
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Components |
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-Supramolecule #1: CCR8 in complex with CCL1 and Gi
Supramolecule | Name: CCR8 in complex with CCL1 and Gi / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#5 |
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Source (natural) | Organism: Homo sapiens (human) |
-Macromolecule #1: C-C motif chemokine 1,C-C chemokine receptor type 8,EGFP fusion p...
Macromolecule | Name: C-C motif chemokine 1,C-C chemokine receptor type 8,EGFP fusion protein type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Human adenovirus C serotype 2 |
Molecular weight | Theoretical: 83.23668 KDa |
Recombinant expression | Organism: Mammalian expression vector Flag-MCS-pcDNA3.1 (others) |
Sequence | String: KSMQVPFSRC CFSFCEQEIP LRAILCYRNT SSICSNEGLI FKLKRGKEAC ALDTVGWVQR HRKMLRHCPS KRKGSGSGSG SGSGSGSGS GSGSGSGSDY TLDLSVTTVT DYYYPDICSS PCDAELIQTN GKLLLAVFYC LLFVFSLLGN SLVILVLVVC K KLRSITDV ...String: KSMQVPFSRC CFSFCEQEIP LRAILCYRNT SSICSNEGLI FKLKRGKEAC ALDTVGWVQR HRKMLRHCPS KRKGSGSGSG SGSGSGSGS GSGSGSGSDY TLDLSVTTVT DYYYPDICSS PCDAELIQTN GKLLLAVFYC LLFVFSLLGN SLVILVLVVC K KLRSITDV YLLNLALSDL LFVFSFPFQT YYLLDQWVFG TVMCKVVSGF YYIGFYSSMF FITLMSVDRY LAVVHAVYAL KV RTIRMGT TLCLAVWLTA IMATIPLLVF YQVASEDGVL QCYSFYNQQT LKWKIFTNFK MNILGLLIPF TIFMFCYIKI LHQ LKRCQN HNKTKAIRLV LIVVIASLLF WVPFNVVLFL TSLHSMHILD GCSISQQLTY ATHVTEIISF THCCVNPVIY AFVG EKFKK HLSEIFQKSC SQIFNYLGRQ MPRESCEKSS SCQQHSSRSS SVDYILGGSD YKDDDDKGGS LEVLFQGPMV SKGEE LFTG VVPILVELDG DVNGHKFSVS GEGEGDATYG KLTLKLICTT GKLPVPWPTL VTTLGYGLQC FARYPDHMKQ HDFFKS AMP EGYVQERTIF FKDDGNYKTR AEVKFEGDTL VNRIELKGID FKEDGNILGH KLEYNYNSHN VYITADKQKN GIKANFK IR HNIEDGGVQL ADHYQQNTPI GDGPVLLPDN HYLSYQSKLS KDPNEKRDHM VLLEFVTAAG ITLGMDELYK GSAWSHPQ F EKGGGSGGGS GGSAWSHPQF EK UniProtKB: C-C motif chemokine 1, C-C chemokine receptor type 8, EGFP |
-Macromolecule #2: Guanine nucleotide-binding protein G(i) subunit alpha-1
Macromolecule | Name: Guanine nucleotide-binding protein G(i) subunit alpha-1 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: 43.182078 KDa |
Recombinant expression | Organism: Escherichia coli (E. coli) |
Sequence | String: MKKHHHHHHH HHHENLYFQG GSMGCTLSAE DKAAVERSKM IDRNLREDGE KAAREVKLLL LGAGESGKST IVKQMKIIHE AGYSEEECK QYKAVVYSNT IQSIIAIIRA MGRLKIDFGD SARADDARQL FVLAGAAEEG FMTAELAGVI KRLWKDSGVQ A CFNRSREY ...String: MKKHHHHHHH HHHENLYFQG GSMGCTLSAE DKAAVERSKM IDRNLREDGE KAAREVKLLL LGAGESGKST IVKQMKIIHE AGYSEEECK QYKAVVYSNT IQSIIAIIRA MGRLKIDFGD SARADDARQL FVLAGAAEEG FMTAELAGVI KRLWKDSGVQ A CFNRSREY QLNDSAAYYL NDLDRIAQPN YIPTQQDVLR TRVKTTGIVE THFTFKDLHF KMFDVGGQRS ERKKWIHCFE GV TAIIFCV ALSDYDLVLA EDEEMNRMHE SMKLFDSICN NKWFTDTSII LFLNKKDLFE EKIKKSPLTI CYPEYAGSNT YEE AAAYIQ CQFEDLNKRK DTKEIYTHFT CATDTKNVQF VFDAVTDVII KNNLKDCGLF UniProtKB: Guanine nucleotide-binding protein G(i) subunit alpha-1 |
-Macromolecule #3: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
Macromolecule | Name: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 39.518121 KDa |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
Sequence | String: MHHHHHHHHG ENLYFQGSSE LDQLRQEAEQ LKNQIRDARK ACADATLSQI TNNIDPVGRI QMRTRRTLRG HLAKIYAMHW GTDSRLLVS ASQDGKLIIW DSYTTNKVHA IPLRSSWVMT CAYAPSGNYV ACGGLDNICS IYNLKTREGN VRVSRELAGH T GYLSCCRF ...String: MHHHHHHHHG ENLYFQGSSE LDQLRQEAEQ LKNQIRDARK ACADATLSQI TNNIDPVGRI QMRTRRTLRG HLAKIYAMHW GTDSRLLVS ASQDGKLIIW DSYTTNKVHA IPLRSSWVMT CAYAPSGNYV ACGGLDNICS IYNLKTREGN VRVSRELAGH T GYLSCCRF LDDNQIVTSS GDTTCALWDI ETGQQTTTFT GHTGDVMSLS LAPDTRLFVS GACDASAKLW DVREGMCRQT FT GHESDIN AICFFPNGNA FATGSDDATC RLFDLRADQE LMTYSHDNII CGITSVSFSK SGRLLLAGYD DFNCNVWDAL KAD RAGVLA GHDNRVSCLG VTDDGMAVAT GSWDSFLKIW N UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 |
-Macromolecule #4: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
Macromolecule | Name: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 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: 7.861143 KDa |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
Sequence | String: MASNNTASIA QARKLVEQLK MEANIDRIKV SKAAADLMAY CEAHAKEDPL LTPVPASENP FREKKFFCAI L UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 |
-Macromolecule #5: scFv fragment
Macromolecule | Name: scFv fragment / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Mus musculus (house mouse) |
Molecular weight | Theoretical: 28.124387 KDa |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
Sequence | String: AGSDVQLVES GGGLVQPGGS RKLSCSASGF AFSSFGMHWV RQAPEKGLEW VAYISSGSGT IYYADTVKGR FTISRDDPKN TLFLQMTSL RSEDTAMYYC VRSIYYYGSS PFDFWGQGTT LTVSSGGSDI VMTQATSSVP VTPGESVSIS CRSSKSLLHS N GNTYLYWF ...String: AGSDVQLVES GGGLVQPGGS RKLSCSASGF AFSSFGMHWV RQAPEKGLEW VAYISSGSGT IYYADTVKGR FTISRDDPKN TLFLQMTSL RSEDTAMYYC VRSIYYYGSS PFDFWGQGTT LTVSSGGSDI VMTQATSSVP VTPGESVSIS CRSSKSLLHS N GNTYLYWF LQRPGQSPQL LIYRMSNLAS GVPDRFSGSG SGTAFTLTIS RLEAEDVGVY YCMQHLEYPL TFGAGTKLEL KA AAGNSLV PRGSHHHHHH HH |
-Macromolecule #6: 2-acetamido-2-deoxy-beta-D-glucopyranose
Macromolecule | Name: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 6 / Number of copies: 1 / Formula: NAG |
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Molecular weight | Theoretical: 221.208 Da |
Chemical component information | ChemComp-NAG: |
-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: FEI FALCON IV (4k x 4k) / Average electron dose: 40.814 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: 1.8 µm / Nominal defocus min: 0.8 µm |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
-Image processing
Startup model | Type of model: OTHER |
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Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 3.1 Å / Resolution method: OTHER / Number images used: 201761 |
Initial angle assignment | Type: OTHER / Details: Ab initio in cryoSPARC |
Final angle assignment | Type: MAXIMUM LIKELIHOOD |