[English] 日本語
Yorodumi- EMDB-12746: Structural basis of the activation of the CC chemokine receptor 5... -
+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-12746 | |||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Title | Structural basis of the activation of the CC chemokine receptor 5 by a chemokine agonist | |||||||||||||||
Map data | ||||||||||||||||
Sample |
| |||||||||||||||
Function / homology | Function and homology information regulation of chronic inflammatory response / CCR4 chemokine receptor binding / chemokine receptor antagonist activity / activation of phospholipase D activity / chemokine (C-C motif) ligand 5 binding / positive regulation of cellular biosynthetic process / 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 receptor antagonist activity / activation of phospholipase D activity / chemokine (C-C motif) ligand 5 binding / positive regulation of cellular biosynthetic process / CCR1 chemokine receptor binding / positive regulation of natural killer cell chemotaxis / negative regulation of macrophage apoptotic process / chemokine receptor binding / signaling / positive regulation of cell-cell adhesion mediated by integrin / Olfactory Signaling Pathway / Sensory perception of sweet, bitter, and umami (glutamate) taste / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / chemokine receptor activity / positive regulation of activation of Janus kinase activity / receptor signaling protein tyrosine kinase activator activity / CCR5 chemokine receptor binding / positive regulation of T cell chemotaxis / positive regulation of homotypic cell-cell adhesion / negative regulation of G protein-coupled receptor signaling pathway / CCR chemokine receptor binding / lymphocyte chemotaxis / Inactivation, recovery and regulation of the phototransduction cascade / Activation of the phototransduction cascade / phosphatidylinositol phospholipase C activity / C-C chemokine receptor activity / negative regulation of T cell apoptotic process / positive regulation of T cell apoptotic process / C-C chemokine binding / neutrophil activation / positive regulation of calcium ion transport / eosinophil chemotaxis / response to cholesterol / positive regulation of innate immune response / cellular response to fibroblast growth factor stimulus / chemokine-mediated signaling pathway / positive regulation of monocyte chemotaxis / Chemokine receptors bind chemokines / release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / 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 / chemokine activity / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / G alpha (12/13) signalling events / G beta:gamma signalling through BTK / ADP signalling through P2Y purinoceptor 12 / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / Thrombin signalling through proteinase activated receptors (PARs) / dendritic cell chemotaxis / Ca2+ pathway / regulation of T cell activation / G alpha (z) signalling events / Extra-nuclear estrogen signaling / G alpha (s) signalling events / G alpha (q) signalling events / G alpha (i) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / leukocyte cell-cell adhesion / Vasopressin regulates renal water homeostasis via Aquaporins / negative regulation of viral genome replication / phospholipase activator activity / positive regulation of macrophage chemotaxis / positive regulation of smooth muscle cell migration / exocytosis / chemoattractant activity / macrophage chemotaxis / Interleukin-10 signaling / monocyte chemotaxis / regulation of insulin secretion / positive regulation of cell adhesion / negative regulation by host of viral transcription / Adenylate cyclase inhibitory pathway / positive regulation of T cell migration / positive regulation of protein localization to cell cortex / positive regulation of translational initiation / positive regulation of viral genome replication / Binding and entry of HIV virion / cellular response to interleukin-1 / regulation of cAMP-mediated signaling / cellular defense response / D2 dopamine receptor binding / G protein-coupled serotonin receptor binding / coreceptor activity / positive regulation of T cell proliferation / positive regulation of phosphorylation / positive regulation of tyrosine phosphorylation of STAT protein / regulation of mitotic spindle organization / cellular response to forskolin / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway Similarity search - Function | |||||||||||||||
Biological species | Homo sapiens (human) / Bos taurus (cattle) / Mus musculus (house mouse) / Bovine (cattle) | |||||||||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.15 Å | |||||||||||||||
Authors | Isaikina P / Tsai C-J / Dietz NB / Pamula F / Goldie KN / Schertler GFX / Maier T / Stahlberg H / Deupi X / Grzesiek S | |||||||||||||||
Funding support | Switzerland, European Union, 4 items
| |||||||||||||||
Citation | Journal: 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 |
|
-Structure visualization
Movie |
Movie viewer |
---|---|
Structure viewer | EM map: SurfViewMolmilJmol/JSmol |
Supplemental images |
-Downloads & links
-EMDB archive
Map data | emd_12746.map.gz | 168.2 MB | EMDB map data format | |
---|---|---|---|---|
Header (meta data) | emd-12746-v30.xml emd-12746.xml | 29.9 KB 29.9 KB | Display Display | EMDB header |
FSC (resolution estimation) | emd_12746_fsc.xml | 12.5 KB | Display | FSC data file |
Images | emd_12746.png | 125 KB | ||
Masks | emd_12746_msk_1.map | 178 MB | Mask map | |
Others | emd_12746_half_map_1.map.gz emd_12746_half_map_2.map.gz | 165 MB 165 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-12746 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-12746 | HTTPS FTP |
-Validation report
Summary document | emd_12746_validation.pdf.gz | 484.3 KB | Display | EMDB validaton report |
---|---|---|---|---|
Full document | emd_12746_full_validation.pdf.gz | 483.8 KB | Display | |
Data in XML | emd_12746_validation.xml.gz | 19.8 KB | Display | |
Data in CIF | emd_12746_validation.cif.gz | 25.3 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-12746 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-12746 | HTTPS FTP |
-Related structure data
Related structure data | 7o7fMC M: atomic model generated by this map C: citing same article (ref.) |
---|---|
Similar structure data |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
---|---|
Related items in Molecule of the Month |
-Map
File | Download / File: emd_12746.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Voxel size | X=Y=Z: 1.112 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Density |
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
|
-Supplemental data
-Mask #1
File | emd_12746_msk_1.map | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Projections & Slices |
| ||||||||||||
Density Histograms |
-Half map: #2
File | emd_12746_half_map_1.map | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Projections & Slices |
| ||||||||||||
Density Histograms |
-Half map: #1
File | emd_12746_half_map_2.map | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Projections & Slices |
| ||||||||||||
Density Histograms |
-Sample components
+Entire : [6P4]CCL5-CCR5-Gi-Fab16
+Supramolecule #1: [6P4]CCL5-CCR5-Gi-Fab16
+Supramolecule #2: Guanine nucleotide-binding protein G(i) subunit alpha-1
+Supramolecule #3: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
+Supramolecule #4: C-C chemokine receptor type 5
+Supramolecule #5: Guanine nucleotide-binding protein G(T) subunit gamma-T1
+Supramolecule #6: C-C motif chemokine 5(0-68)
+Supramolecule #7: Fab
+Macromolecule #1: Guanine nucleotide-binding protein G(i) subunit alpha-1
+Macromolecule #2: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
+Macromolecule #3: C-C chemokine receptor type 5
+Macromolecule #4: Guanine nucleotide-binding protein G(T) subunit gamma-T1
+Macromolecule #5: C-C motif chemokine 5
+Macromolecule #6: Fab antibody fragment heavy chain
+Macromolecule #7: Fab antibody fragment light chain
-Experimental details
-Structure determination
Method | cryo EM |
---|---|
Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Concentration | 2.5 mg/mL | ||||||||
---|---|---|---|---|---|---|---|---|---|
Buffer | pH: 7.5 Component:
| ||||||||
Grid | Model: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 200 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Pressure: 0.025 kPa | ||||||||
Vitrification | Cryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV |
-Electron microscopy
Microscope | TFS GLACIOS |
---|---|
Image recording | Film or detector model: GATAN K3 (6k x 4k) / Number grids imaged: 1 / Number real images: 2466 / Average electron dose: 49.0 e/Å2 |
Electron beam | Acceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD |
-Image processing
-Atomic model buiding 1
Initial model |
| ||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|
Refinement | Space: REAL / Protocol: FLEXIBLE FIT | ||||||||||
Output model | PDB-7o7f: |