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- PDB-6wwz: Cryo-EM structure of the human chemokine receptor CCR6 in complex... -

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Basic information

Entry
Database: PDB / ID: 6wwz
TitleCryo-EM structure of the human chemokine receptor CCR6 in complex with CCL20 and a Go protein
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • C-C chemokine receptor type 6,C-C chemokine receptor type 6
  • C-C motif chemokine 20
  • scFv16
KeywordsMEMBRANE PROTEIN / GPCR / Chemokine / Chemokine receptor / Complex
Function / homology
Function and homology information


isotype switching to IgA isotypes / DN3 thymocyte differentiation / thymocyte migration / positive regulation of flagellated sperm motility involved in capacitation / CCR6 chemokine receptor binding / Beta defensins / sperm principal piece / positive regulation of dendritic cell chemotaxis / regulation of T cell migration / DN2 thymocyte differentiation ...isotype switching to IgA isotypes / DN3 thymocyte differentiation / thymocyte migration / positive regulation of flagellated sperm motility involved in capacitation / CCR6 chemokine receptor binding / Beta defensins / sperm principal piece / positive regulation of dendritic cell chemotaxis / regulation of T cell migration / DN2 thymocyte differentiation / lymphocyte migration / chemokine receptor activity / leukocyte migration involved in inflammatory response / mu-type opioid receptor binding / C-C chemokine receptor activity / corticotropin-releasing hormone receptor 1 binding / C-C chemokine binding / G-protein activation / Activation of the phototransduction cascade / Glucagon-type ligand receptors / Thromboxane signalling through TP receptor / Sensory perception of sweet, bitter, and umami (glutamate) taste / G beta:gamma signalling through PI3Kgamma / G beta:gamma signalling through CDC42 / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Ca2+ pathway / G alpha (z) signalling events / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / vesicle docking involved in exocytosis / Adrenaline,noradrenaline inhibits insulin secretion / ADP signalling through P2Y purinoceptor 12 / G alpha (q) signalling events / chemokine activity / G alpha (i) signalling events / Chemokine receptors bind chemokines / Thrombin signalling through proteinase activated receptors (PARs) / dendritic cell chemotaxis / G protein-coupled dopamine receptor signaling pathway / photoreceptor outer segment membrane / spectrin binding / sperm plasma membrane / regulation of heart contraction / parallel fiber to Purkinje cell synapse / Interleukin-10 signaling / alkylglycerophosphoethanolamine phosphodiesterase activity / humoral immune response / sperm flagellum / photoreceptor outer segment / positive regulation of T cell migration / postsynaptic modulation of chemical synaptic transmission / cellular defense response / negative regulation of insulin secretion / T cell migration / G protein-coupled serotonin receptor binding / adenylate cyclase regulator activity / adenylate cyclase-inhibiting serotonin receptor signaling pathway / muscle contraction / photoreceptor inner segment / cardiac muscle cell apoptotic process / sperm midpiece / GABA-ergic synapse / cell chemotaxis / locomotory behavior / calcium-mediated signaling / electron transport chain / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / G-protein beta/gamma-subunit complex binding / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / 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 / G beta:gamma signalling through CDC42 / Glucagon signaling in metabolic regulation / G beta:gamma signalling through BTK / ADP signalling through P2Y purinoceptor 12 / chemotaxis / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / G alpha (z) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / cellular response to catecholamine stimulus / ADORA2B mediated anti-inflammatory cytokines production / ADP signalling through P2Y purinoceptor 1 / G beta:gamma signalling through PI3Kgamma / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / adenylate cyclase-activating dopamine receptor signaling pathway / GPER1 signaling / cellular response to prostaglandin E stimulus / G-protein beta-subunit binding / heterotrimeric G-protein complex / G alpha (12/13) signalling events / sensory perception of taste
Similarity search - Function
CC chemokine receptor 6 / Chemokine CC, DCCL motif-cointaining domain / Transducin (heterotrimeric G protein), gamma chain / G Protein Gi Gamma 2 / CC chemokine, conserved site / Small cytokines (intercrine/chemokine) C-C subfamily signature. / Chemokine receptor family / : / Chemokine beta/gamma/delta / Intercrine alpha family (small cytokine C-X-C) (chemokine CXC). ...CC chemokine receptor 6 / Chemokine CC, DCCL motif-cointaining domain / Transducin (heterotrimeric G protein), gamma chain / G Protein Gi Gamma 2 / CC chemokine, conserved site / Small cytokines (intercrine/chemokine) C-C subfamily signature. / Chemokine receptor family / : / Chemokine beta/gamma/delta / Intercrine alpha family (small cytokine C-X-C) (chemokine CXC). / Chemokine interleukin-8-like domain / Chemokine interleukin-8-like superfamily / Small cytokines (intecrine/chemokine), interleukin-8 like / OB fold (Dihydrolipoamide Acetyltransferase, E2P) - #40 / Cytochrome b562 / Cytochrome b562 / Cytochrome c/b562 / G-protein alpha subunit, group I / YVTN repeat-like/Quinoprotein amine dehydrogenase / 7 Propeller / Methylamine Dehydrogenase; Chain H / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G-alpha domain profile. / G protein alpha subunit / Few Secondary Structures / Irregular / 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 / Guanine nucleotide-binding protein, beta subunit / G-protein, beta subunit / G-protein coupled receptors family 1 signature. / OB fold (Dihydrolipoamide Acetyltransferase, E2P) / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. / 7 transmembrane receptor (rhodopsin family) / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / P-loop containing nucleotide triphosphate hydrolases / WD domain, G-beta repeat / 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 / Beta Barrel / Rossmann fold / P-loop containing nucleoside triphosphate hydrolase / 3-Layer(aba) Sandwich / Mainly Beta / Alpha Beta
Similarity search - Domain/homology
Guanine nucleotide-binding protein G(o) subunit alpha / Soluble cytochrome b562 / C-C chemokine receptor type 6 / Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / C-C motif chemokine 20
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
Homo sapiens (human)
Mus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.34 Å
AuthorsWasilko, D.J. / Johnson, Z.L. / Ammirati, M. / Han, S. / Wu, H.
CitationJournal: Nat Commun / Year: 2020
Title: Structural basis for chemokine receptor CCR6 activation by the endogenous protein ligand CCL20.
Authors: David Jonathan Wasilko / Zachary Lee Johnson / Mark Ammirati / Ye Che / Matthew C Griffor / Seungil Han / Huixian Wu /
Abstract: Chemokines are important protein-signaling molecules that regulate various immune responses by activating chemokine receptors which belong to the G protein-coupled receptor (GPCR) superfamily. ...Chemokines are important protein-signaling molecules that regulate various immune responses by activating chemokine receptors which belong to the G protein-coupled receptor (GPCR) superfamily. Despite the substantial progression of our structural understanding of GPCR activation by small molecule and peptide agonists, the molecular mechanism of GPCR activation by protein agonists remains unclear. Here, we present a 3.3-Å cryo-electron microscopy structure of the human chemokine receptor CCR6 bound to its endogenous ligand CCL20 and an engineered Go. CCL20 binds in a shallow extracellular pocket, making limited contact with the core 7-transmembrane (TM) bundle. The structure suggests that this mode of binding induces allosterically a rearrangement of a noncanonical toggle switch and the opening of the intracellular crevice for G protein coupling. Our results demonstrate that GPCR activation by a protein agonist does not always require substantial interactions between ligand and the 7TM core region.
History
DepositionMay 9, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 24, 2020Provider: repository / Type: Initial release
Revision 1.1Jul 1, 2020Group: Database references / Category: citation / citation_author
Item: _citation.page_first / _citation.page_last ..._citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID
Revision 1.2Oct 30, 2024Group: Data collection / Database references ...Data collection / Database references / Refinement description / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / em_3d_fitting_list / em_admin / pdbx_entry_details / pdbx_initial_refinement_model / pdbx_modification_feature
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _em_3d_fitting_list.accession_code / _em_3d_fitting_list.initial_refinement_model_id / _em_3d_fitting_list.source_name / _em_3d_fitting_list.type / _em_admin.last_update

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Structure visualization

Movie
  • Deposited structure unit
  • Imaged by Jmol
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  • Superimposition on EM map
  • EMDB-21950
  • Imaged by UCSF Chimera
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Structure viewerMolecule:
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Assembly

Deposited unit
B: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
C: C-C motif chemokine 20
Y: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
A: Guanine nucleotide-binding protein G(o) subunit alpha,Guanine nucleotide-binding protein G(o) subunit alpha
S: scFv16
R: C-C chemokine receptor type 6,C-C chemokine receptor type 6


Theoretical massNumber of molelcules
Total (without water)173,5086
Polymers173,5086
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area13150 Å2
ΔGint-84 kcal/mol
Surface area60610 Å2

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Components

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Guanine nucleotide-binding protein ... , 3 types, 3 molecules BYA

#1: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 38744.371 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rattus norvegicus (Norway rat) / Gene: Gnb1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P54311
#3: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2


Mass: 7563.750 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rattus norvegicus (Norway rat) / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P59768*PLUS
#4: Protein Guanine nucleotide-binding protein G(o) subunit alpha,Guanine nucleotide-binding protein G(o) subunit alpha


Mass: 28195.869 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNAO1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P09471

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Protein , 2 types, 2 molecules CR

#2: Protein C-C motif chemokine 20 / Beta-chemokine exodus-1 / CC chemokine LARC / Liver and activation-regulated chemokine / Macrophage ...Beta-chemokine exodus-1 / CC chemokine LARC / Liver and activation-regulated chemokine / Macrophage inflammatory protein 3 alpha / MIP-3-alpha / Small-inducible cytokine A20


Mass: 8043.568 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CCL20, LARC, MIP3A, SCYA20 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P78556
#6: Protein C-C chemokine receptor type 6,C-C chemokine receptor type 6 / CCR-6 / Chemokine receptor-like 3 / CKR-L3 / DRY6 / G-protein coupled receptor 29 / GPR-CY4 / ...CCR-6 / Chemokine receptor-like 3 / CKR-L3 / DRY6 / G-protein coupled receptor 29 / GPR-CY4 / GPRCY4 / LARC receptor


Mass: 60064.574 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CCR6, CKRL3, CMKBR6, GPR29, STRL22 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P51684, UniProt: P0ABE7*PLUS

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Antibody , 1 types, 1 molecules S

#5: Antibody scFv16


Mass: 30895.527 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)

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Details

Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

Component
IDNameTypeEntity IDParent-IDSource
1CCR6-CCL20-Go complexCOMPLEXall0MULTIPLE SOURCES
2Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2COMPLEX#1, #31RECOMBINANT
3C-C motif chemokine 20, Guanine nucleotide-binding protein G(o) subunit alpha,Guanine nucleotide-binding protein G(o) subunit alpha, C-C chemokine receptor type 6,C-C chemokine receptor type 6COMPLEX#2, #4, #61RECOMBINANT
4scFv16COMPLEX#51RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
12Rattus norvegicus (Norway rat)10116
23Homo sapiens (human)9606
34Mus musculus (house mouse)10090
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
12Spodoptera frugiperda (fall armyworm)7108
23Spodoptera frugiperda (fall armyworm)7108
34Spodoptera frugiperda (fall armyworm)7108
Buffer solutionpH: 7.5
Buffer component
IDConc.NameFormulaBuffer-ID
120 mMHEPESHEPES1
2100 mMSodium ChlorideNaCl1
30.001 %Lauryl Maltose Neopentyl GlycolLMNG1
40.0002 %Cholesteryl HemisuccinateCHS1
50.2 mg/mlFLAG Peptide1
63 mMFluorinated Fos-Choline-81
SpecimenConc.: 6.8 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 165000 X / Nominal defocus max: 2000 nm / Nominal defocus min: 600 nm / Cs: 2.7 mm / C2 aperture diameter: 100 µm
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Temperature (max): 100 K / Temperature (min): 80 K
Image recordingAverage exposure time: 8 sec. / Electron dose: 81 e/Å2 / Detector mode: SUPER-RESOLUTION / Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 5303
EM imaging opticsEnergyfilter name: GIF Quantum LS / Energyfilter slit width: 20 eV
Image scansWidth: 3838 / Height: 3710 / Movie frames/image: 50 / Used frames/image: 1-50

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Processing

SoftwareName: REFMAC / Version: 5.8.0258 / Classification: refinement
EM software
IDNameVersionCategoryFitting-IDDetails
1RELION3.0.5particle selection
2SerialEM3.8.0 betaimage acquisition
4CTFFIND4.1CTF correction
7UCSF Chimera1.14model fitting1
8Coot0.8.9.2model fitting1
10RELION3.0.5initial Euler assignment
11RELION3.0.5final Euler assignment
12RELION3.0.5classification
13RELION3.0.53D reconstruction
20Coot0.8.9.2model refinement1
21PHENIXdev-3026model refinement1
22REFMACCCP4 7.0model refinement1Refmac5
34UCSF Chimera1.14model fitting2
35Coot0.8.9.2model fitting2
36Coot0.8.9.2model refinement2
37PHENIXdev-3026model refinement2
38REFMACCCP4 7.0model refinement2Refmac5
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 1000382
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.34 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 230450 / Num. of class averages: 1 / Symmetry type: POINT
Atomic model building
IDProtocolSpaceB valueTarget criteria
1RIGID BODY FITREAL
2FLEXIBLE FITREAL123.52Correlation coefficient
Atomic model building

Source name: PDB / Type: experimental model

IDPDB-IDPdb chain-ID 3D fitting-IDAccession codeInitial refinement model-ID
16G79

6g79

16G791
26DDE

6dde

E16DDE2
31M8A

1m8a

A11M8A3
46G79

6g79

26G791
56DDE

6dde

E26DDE2
61M8A

1m8a

A21M8A3
RefinementResolution: 3.34→154 Å / Cor.coef. Fo:Fc: 0.86 / SU B: 109.675 / SU ML: 2.255 / ESU R: 0.432
Stereochemistry target values: MAXIMUM LIKELIHOOD WITH PHASES
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflection
Rwork0.3813 --
obs0.3813 117557 100 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 107.024 Å2
Baniso -1Baniso -2Baniso -3
1-0.32 Å20.36 Å2-0.51 Å2
2--0.51 Å2-1.59 Å2
3----0.84 Å2

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