+Open data
-Basic information
Entry | Database: PDB / ID: 8u1u | ||||||
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Title | Structure of a class A GPCR/agonist complex | ||||||
Components |
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Keywords | STRUCTURAL PROTEIN / GPCR / agonist | ||||||
Function / homology | Function and homology information chemokine receptor activity / C-C chemokine receptor activity / CCR chemokine receptor binding / lymphocyte chemotaxis / C-C chemokine binding / eosinophil chemotaxis / chemokine-mediated signaling pathway / positive regulation of monocyte chemotaxis / Chemokine receptors bind chemokines / chemokine activity ...chemokine receptor activity / C-C chemokine receptor activity / CCR chemokine receptor binding / lymphocyte chemotaxis / C-C chemokine binding / eosinophil chemotaxis / chemokine-mediated signaling pathway / positive regulation of monocyte chemotaxis / Chemokine receptors bind chemokines / chemokine activity / positive regulation of interleukin-17 production / monocyte chemotaxis / Adenylate cyclase inhibitory pathway / positive regulation of protein localization to cell cortex / regulation of cAMP-mediated signaling / D2 dopamine receptor binding / G protein-coupled serotonin receptor binding / cellular response to interleukin-1 / coreceptor activity / regulation of mitotic spindle organization / cellular response to forskolin / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / viral process / cell chemotaxis / bioluminescence / neutrophil chemotaxis / generation of precursor metabolites and energy / 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 / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / G-protein activation / G protein-coupled acetylcholine receptor signaling pathway / 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 / intracellular calcium ion homeostasis / ADP signalling through P2Y purinoceptor 12 / G beta:gamma signalling through BTK / Sensory perception of sweet, bitter, and umami (glutamate) taste / response to peptide hormone / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / photoreceptor disc membrane / Adrenaline,noradrenaline inhibits insulin secretion / Glucagon-type ligand receptors / Vasopressin regulates renal water homeostasis via Aquaporins / G alpha (z) signalling events / cellular response to catecholamine stimulus / positive regulation of inflammatory response / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / cellular response to type II interferon / adenylate cyclase-activating dopamine receptor signaling pathway / ADP signalling through P2Y purinoceptor 1 / G beta:gamma signalling through PI3Kgamma / cellular response to prostaglandin E stimulus / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / sensory perception of taste / GPER1 signaling / GDP binding / G-protein beta-subunit binding / heterotrimeric G-protein complex / Inactivation, recovery and regulation of the phototransduction cascade / extracellular vesicle / G alpha (12/13) signalling events / chemotaxis / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / retina development in camera-type eye / GTPase binding / Ca2+ pathway / phospholipase C-activating G protein-coupled receptor signaling pathway / cellular response to tumor necrosis factor / cell cortex / midbody / positive regulation of cytosolic calcium ion concentration / G alpha (i) signalling events / fibroblast proliferation / G alpha (s) signalling events / G alpha (q) signalling events / Ras protein signal transduction / cell population proliferation / Extra-nuclear estrogen signaling / positive regulation of ERK1 and ERK2 cascade / cell adhesion / immune response / cell cycle / inflammatory response / G protein-coupled receptor signaling pathway / cell division / lysosomal membrane / external side of plasma membrane Similarity search - Function | ||||||
Biological species | Homo sapiens (human) Human adenovirus C serotype 2 Mus musculus (house mouse) | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.1 Å | ||||||
Authors | Sun, D. / Johnson, M. / Masureel, M. | ||||||
Funding support | 1items
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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
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 8u1u.cif.gz | 239.2 KB | Display | PDBx/mmCIF format |
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PDB format | pdb8u1u.ent.gz | 181.1 KB | Display | PDB format |
PDBx/mmJSON format | 8u1u.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/u1/8u1u ftp://data.pdbj.org/pub/pdb/validation_reports/u1/8u1u | HTTPS FTP |
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-Related structure data
Related structure data | 41829MC 8tlmC M: map data used to model this data C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
-Guanine nucleotide-binding protein ... , 3 types, 3 molecules BCD
#2: Protein | Mass: 43182.078 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: GNAI1 / Production host: Escherichia coli (E. coli) / References: UniProt: P63096 |
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#3: Protein | Mass: 39518.121 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: GNB1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P62873 |
#4: Protein | Mass: 7861.143 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: GNG2 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P59768 |
-Protein / Antibody / Sugars , 3 types, 3 molecules AE
#1: Protein | Mass: 83236.680 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human), (gene. exp.) Human adenovirus C serotype 2 Gene: CCL1, CCR8 Production host: Mammalian expression vector Flag-MCS-pcDNA3.1 (others) References: UniProt: P22362, UniProt: P51685, UniProt: A0A6M5E0N3 |
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#5: Antibody | Mass: 28124.387 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Mus musculus (house mouse) / Production host: Spodoptera frugiperda (fall armyworm) |
#6: Sugar | ChemComp-NAG / |
-Details
Has ligand of interest | Y |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
Component | Name: CCR8 in complex with CCL1 and Gi / Type: COMPLEX / Entity ID: #1-#5 / Source: MULTIPLE SOURCES |
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Source (natural) | Organism: Homo sapiens (human) |
Source (recombinant) | Organism: Mammalian expression vector Flag-MCS-pcDNA3.1 (others) |
Buffer solution | pH: 7.5 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Vitrification | Cryogen name: ETHANE |
-Electron microscopy imaging
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 1800 nm / Nominal defocus min: 800 nm |
Image recording | Electron dose: 40.814 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k) |
-Processing
CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION |
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3D reconstruction | Resolution: 3.1 Å / Resolution method: OTHER / Num. of particles: 201761 / Symmetry type: POINT |