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- PDB-7o7f: Structural basis of the activation of the CC chemokine receptor 5... -

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Basic information

Entry
Database: PDB / ID: 7o7f
TitleStructural basis of the activation of the CC chemokine receptor 5 by a chemokine agonist
Components
  • (Fab antibody fragment ...) x 2
  • (Guanine nucleotide-binding protein ...) x 3
  • C-C chemokine receptor type 5
  • C-C motif chemokine 5
KeywordsSIGNALING PROTEIN / G protein-coupled receptor (GPCR) / CCR5 / CCL5/RANTES / HIV entry / AIDS / membrane protein structure / MEMBRANE PROTEIN
Function / homology
Function and homology information


regulation of chronic inflammatory response / CCR4 chemokine receptor binding / chemokine (C-C motif) ligand 5 signaling pathway / activation of phospholipase D activity / chemokine receptor antagonist activity / chemokine (C-C motif) ligand 5 binding / CCR1 chemokine receptor binding / positive regulation of natural killer cell chemotaxis / negative regulation of macrophage apoptotic process / chemokine receptor binding ...regulation of chronic inflammatory response / CCR4 chemokine receptor binding / chemokine (C-C motif) ligand 5 signaling pathway / activation of phospholipase D activity / chemokine receptor antagonist activity / chemokine (C-C motif) ligand 5 binding / CCR1 chemokine receptor binding / positive regulation of natural killer cell chemotaxis / negative regulation of macrophage apoptotic process / chemokine receptor binding / Olfactory Signaling Pathway / receptor signaling protein tyrosine kinase activator activity / chemokine receptor activity / CCR5 chemokine receptor binding / Sensory perception of sweet, bitter, and umami (glutamate) taste / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / positive regulation of receptor signaling pathway via STAT / positive regulation of T cell chemotaxis / CCR chemokine receptor binding / positive regulation of cell-cell adhesion mediated by integrin / eye photoreceptor cell development / signaling / positive regulation of homotypic cell-cell adhesion / Inactivation, recovery and regulation of the phototransduction cascade / neutrophil activation / positive regulation of G protein-coupled receptor signaling pathway / Activation of the phototransduction cascade / C-C chemokine receptor activity / phosphatidylinositol-4,5-bisphosphate phospholipase C activity / negative regulation of T cell apoptotic process / chemokine-mediated signaling pathway / positive regulation of T cell apoptotic process / C-C chemokine binding / eosinophil chemotaxis / positive regulation of calcium ion transport / response to cholesterol / positive regulation of monocyte chemotaxis / positive regulation of innate immune response / cell surface receptor signaling pathway via STAT / chemokine activity / regulation of T cell activation / Chemokine receptors bind chemokines / Activation of G protein gated Potassium channels / G-protein activation / G beta:gamma signalling through PI3Kgamma / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through PLC beta / ADP signalling through P2Y purinoceptor 1 / Thromboxane signalling through TP receptor / Presynaptic function of Kainate receptors / G beta:gamma signalling through CDC42 / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / G alpha (12/13) signalling events / Glucagon-type ligand receptors / G beta:gamma signalling through BTK / ADP signalling through P2Y purinoceptor 12 / Adrenaline,noradrenaline inhibits insulin secretion / dendritic cell chemotaxis / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / Ca2+ pathway / Thrombin signalling through proteinase activated receptors (PARs) / G alpha (z) signalling events / Extra-nuclear estrogen signaling / G alpha (s) signalling events / negative regulation of G protein-coupled receptor signaling pathway / G alpha (q) signalling events / leukocyte cell-cell adhesion / phospholipase activator activity / negative regulation of viral genome replication / G alpha (i) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / positive regulation of smooth muscle cell migration / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / Vasopressin regulates renal water homeostasis via Aquaporins / Interleukin-10 signaling / positive regulation of macrophage chemotaxis / chemoattractant activity / macrophage chemotaxis / exocytosis / monocyte chemotaxis / positive regulation of translational initiation / cellular response to interleukin-1 / cellular response to fibroblast growth factor stimulus / negative regulation by host of viral transcription / phototransduction / positive regulation of TOR signaling / Binding and entry of HIV virion / positive regulation of T cell migration / cellular defense response / positive regulation of viral genome replication / positive regulation of protein localization to cell cortex / Adenylate cyclase inhibitory pathway / positive regulation of T cell proliferation / T cell migration / coreceptor activity / D2 dopamine receptor binding / response to prostaglandin E / G protein-coupled serotonin receptor binding / adenylate cyclase regulator activity
Similarity search - Function
CC chemokine receptor 5 / 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 ...CC chemokine receptor 5 / 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 / 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 / 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. / 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. / 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 / Immunoglobulins / Immunoglobulin-like / Sandwich / P-loop containing nucleoside triphosphate hydrolase / Mainly Beta
Similarity search - Domain/homology
Guanine nucleotide-binding protein G(T) subunit gamma-T1 / C-C motif chemokine 5 / C-C chemokine receptor type 5 / Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Guanine nucleotide-binding protein G(i) subunit alpha-1
Similarity search - Component
Biological speciesHomo sapiens (human)
Mus musculus (house mouse)
Bos taurus (domestic cattle)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.15 Å
AuthorsIsaikina, P. / Tsai, C.-J. / Dietz, N.B. / Pamula, F. / Goldie, K.N. / Schertler, G.F.X. / Maier, T. / Stahlberg, H. / Deupi, X. / Grzesiek, S.
Funding support Switzerland, European Union, 4items
OrganizationGrant numberCountry
Swiss National Science Foundation31-149927 Switzerland
Swiss National Science Foundation31-173089 Switzerland
European Commission6th Framework EMPROEuropean Union
European Commission7th Framework CHAARMEuropean Union
CitationJournal: Sci Adv / Year: 2021
Title: Structural basis of the activation of the CC chemokine receptor 5 by a chemokine agonist.
Authors: Polina Isaikina / Ching-Ju Tsai / Nikolaus Dietz / Filip Pamula / Anne Grahl / Kenneth N Goldie / Ramon Guixà-González / Camila Branco / Marianne Paolini-Bertrand / Nicolas Calo / Fabrice ...Authors: Polina Isaikina / Ching-Ju Tsai / Nikolaus Dietz / Filip Pamula / Anne Grahl / Kenneth N Goldie / Ramon Guixà-González / Camila Branco / Marianne Paolini-Bertrand / Nicolas Calo / Fabrice Cerini / Gebhard F X Schertler / Oliver Hartley / Henning Stahlberg / Timm Maier / Xavier Deupi / Stephan Grzesiek /
Abstract: The human CC chemokine receptor 5 (CCR5) is a G protein-coupled receptor (GPCR) that plays a major role in inflammation and is involved in cancer, HIV, and COVID-19. Despite its importance as a drug ...The human CC chemokine receptor 5 (CCR5) is a G protein-coupled receptor (GPCR) that plays a major role in inflammation and is involved in cancer, HIV, and COVID-19. Despite its importance as a drug target, the molecular activation mechanism of CCR5, i.e., how chemokine agonists transduce the activation signal through the receptor, is yet unknown. Here, we report the cryo-EM structure of wild-type CCR5 in an active conformation bound to the chemokine super-agonist [6P4]CCL5 and the heterotrimeric G protein. The structure provides the rationale for the sequence-activity relation of agonist and antagonist chemokines. The N terminus of agonist chemokines pushes onto specific structural motifs at the bottom of the orthosteric pocket that activate the canonical GPCR microswitch network. This activation mechanism differs substantially from other CC chemokine receptors that bind chemokines with shorter N termini in a shallow binding mode involving unique sequence signatures and a specialized activation mechanism.
History
DepositionApr 13, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 30, 2021Provider: repository / Type: Initial release
Revision 1.1Mar 16, 2022Group: Database references / Category: database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.2Oct 23, 2024Group: Data collection / Refinement description / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / em_3d_fitting_list / em_admin / pdbx_entry_details / pdbx_initial_refinement_model / pdbx_modification_feature
Item: _em_3d_fitting_list.accession_code / _em_3d_fitting_list.initial_refinement_model_id ..._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 / _pdbx_entry_details.has_protein_modification

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Structure visualization

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  • Deposited structure unit
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  • EMDB-12746
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Structure viewerMolecule:
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Assembly

Deposited unit
A: Guanine nucleotide-binding protein G(i) subunit alpha-1
B: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
C: C-C chemokine receptor type 5
G: Guanine nucleotide-binding protein G(T) subunit gamma-T1
I: C-C motif chemokine 5
H: Fab antibody fragment heavy chain
F: Fab antibody fragment light chain


Theoretical massNumber of molelcules
Total (without water)184,4367
Polymers184,4367
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area18120 Å2
ΔGint-107 kcal/mol
Surface area61720 Å2
MethodPISA

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Components

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

#1: Protein Guanine nucleotide-binding protein G(i) subunit alpha-1 / Adenylate cyclase-inhibiting G alpha protein


Mass: 40415.031 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 BL21(DE3) (bacteria) / References: UniProt: P63096
#2: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 37416.930 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Bos taurus (domestic cattle) / References: UniProt: P62871
#4: Protein Guanine nucleotide-binding protein G(T) subunit gamma-T1 / Transducin gamma chain


Mass: 8556.918 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Details: UNP P02698 / Source: (natural) Bos taurus (domestic cattle) / References: UniProt: P02698

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Protein , 2 types, 2 molecules CI

#3: Protein C-C chemokine receptor type 5 / C-C CKR-5 / CC-CKR-5 / CCR-5 / CCR5 / CHEMR13 / HIV-1 fusion coreceptor


Mass: 42726.168 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: UNP P51681 / Source: (gene. exp.) Homo sapiens (human) / Gene: CCR5, CMKBR5 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P51681
#5: Protein C-C motif chemokine 5 / EoCP / Eosinophil chemotactic cytokine / SIS-delta / Small-inducible cytokine A5 / T cell-specific ...EoCP / Eosinophil chemotactic cytokine / SIS-delta / Small-inducible cytokine A5 / T cell-specific protein P228 / TCP228 / T-cell-specific protein RANTES


Mass: 7857.123 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: UNP P13501 / Source: (gene. exp.) Homo sapiens (human) / Gene: CCL5, D17S136E, SCYA5 / Production host: Escherichia coli (E. coli) / References: UniProt: P13501

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Antibody , 2 types, 2 molecules HF

#6: Antibody Fab antibody fragment heavy chain


Mass: 23542.248 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Mus musculus (house mouse)
#7: Antibody Fab antibody fragment light chain


Mass: 23921.592 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Mus musculus (house mouse)

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Details

Has ligand of interestN
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
1[6P4]CCL5-CCR5-Gi-Fab16COMPLEXall0MULTIPLE SOURCES
2Guanine nucleotide-binding protein G(i) subunit alpha-1COMPLEX#11RECOMBINANT
3Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1COMPLEX#21NATURAL
4C-C chemokine receptor type 5COMPLEX#31RECOMBINANT
5Guanine nucleotide-binding protein G(T) subunit gamma-T1COMPLEX#41NATURAL
6C-C motif chemokine 5(0-68)COMPLEX#51RECOMBINANT
7FabCOMPLEX#6-#71RECOMBINANT
Molecular weightUnits: KILODALTONS/NANOMETER / Experimental value: NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
12Homo sapiens (human)9606
24Homo sapiens (human)9606
36Homo sapiens (human)9606
47Mus musculus (house mouse)10090
53Bos taurus (domestic cattle)9913
65Bos taurus (domestic cattle)9913
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
12Escherichia coli BL21(DE3) (bacteria)469008
24Spodoptera frugiperda (fall armyworm)7108
36Escherichia coli (E. coli)562
47Mus musculus (house mouse)10090
Buffer solutionpH: 7.5
Buffer component
IDConc.FormulaBuffer-ID
125 mMHEPES1
2150 mMNaCl1
30.01 %LMNG1
SpecimenConc.: 2.5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 200 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

MicroscopyModel: TFS GLACIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD
Image recordingElectron dose: 49 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) / Num. of grids imaged: 1 / Num. of real images: 2466

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Processing

SoftwareName: PHENIX / Version: 1.19_4092: / Classification: refinement
EM software
IDNameVersionCategoryFitting-ID
7Coot0.9model fitting1
12cryoSPARC3.13D reconstruction
14PHENIX1.19model refinement1
22UCSF Chimeramodel fitting2
28PHENIX1.19model refinement2
CTF correctionType: NONE
3D reconstructionResolution: 3.15 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 345458 / Algorithm: FOURIER SPACE / Symmetry type: POINT
Atomic model building
IDProtocolSpace
1FLEXIBLE FITREAL
2RIGID BODY FITREAL
Atomic model building

Source name: PDB / Type: experimental model

IDPDB-IDPdb chain-ID 3D fitting-IDAccession codeInitial refinement model-IDPdb chain residue range
15UIW

5uiw

C15UIW1
25KDO

5kdo

A15KDO2
35KDO

5kdo

B15KDO2
45KDO

5kdo

G15KDO2
55UIW

5uiw

I25UIW111-69
66QNK

6qnk

H26QNK3
76QNK

6qnk

F26QNK3
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00311421
ELECTRON MICROSCOPYf_angle_d0.52115479
ELECTRON MICROSCOPYf_dihedral_angle_d4.851540
ELECTRON MICROSCOPYf_chiral_restr0.0391747
ELECTRON MICROSCOPYf_plane_restr0.0031960

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