[English] 日本語
Yorodumi- EMDB-25389: Structure of the orexin-2 receptor(OX2R) bound to TAK-925, Gi and... -
+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-25389 | |||||||||
---|---|---|---|---|---|---|---|---|---|---|
Title | Structure of the orexin-2 receptor(OX2R) bound to TAK-925, Gi and scFv16 | |||||||||
Map data | Orexin-2 receptor (OX2R) bound to TAK-925, Gi and scFv16 | |||||||||
Sample |
| |||||||||
Function / homology | Function and homology information regulation of circadian sleep/wake cycle, wakefulness / circadian sleep/wake cycle process / orexin receptor activity / Orexin and neuropeptides FF and QRFP bind to their respective receptors / neuropeptide receptor activity / Olfactory Signaling Pathway / Sensory perception of sweet, bitter, and umami (glutamate) taste / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / Activation of the phototransduction cascade / feeding behavior ...regulation of circadian sleep/wake cycle, wakefulness / circadian sleep/wake cycle process / orexin receptor activity / Orexin and neuropeptides FF and QRFP bind to their respective receptors / neuropeptide receptor activity / Olfactory Signaling Pathway / Sensory perception of sweet, bitter, and umami (glutamate) taste / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / Activation of the phototransduction cascade / feeding behavior / locomotion / 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 / 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) / Ca2+ pathway / 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 / Vasopressin regulates renal water homeostasis via Aquaporins / peptide hormone binding / neuropeptide signaling pathway / 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 / regulation of mitotic spindle organization / cellular response to hormone stimulus / cellular response to forskolin / regulation of cytosolic calcium ion concentration / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / peptide binding / Regulation of insulin secretion / G protein-coupled receptor binding / G-protein beta/gamma-subunit complex binding / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / response to peptide hormone / ADP signalling through P2Y purinoceptor 12 / photoreceptor disc membrane / Adrenaline,noradrenaline inhibits insulin secretion / G alpha (z) signalling events / cellular response to catecholamine stimulus / ADORA2B mediated anti-inflammatory cytokines production / adenylate cyclase-activating dopamine receptor signaling pathway / cellular response to prostaglandin E stimulus / GPER1 signaling / GDP binding / G-protein beta-subunit binding / heterotrimeric G-protein complex / signaling receptor complex adaptor activity / phospholipase C-activating G protein-coupled receptor signaling pathway / cell cortex / midbody / G alpha (i) signalling events / G alpha (s) signalling events / G alpha (q) signalling events / chemical synaptic transmission / Extra-nuclear estrogen signaling / G protein-coupled receptor signaling pathway / cell division / lysosomal membrane / GTPase activity / centrosome / synapse / nucleolus / GTP binding / magnesium ion binding / extracellular exosome / nucleoplasm / membrane / plasma membrane / cytoplasm Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) / Bos taurus (cattle) / synthetic construct (others) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.17 Å | |||||||||
Authors | McGrath AP / Kang Y / Flinspach M | |||||||||
Funding support | 1 items
| |||||||||
Citation | Journal: Nat Commun / Year: 2022 Title: Molecular mechanism of the wake-promoting agent TAK-925. Authors: Jie Yin / Yanyong Kang / Aaron P McGrath / Karen Chapman / Megan Sjodt / Eiji Kimura / Atsutoshi Okabe / Tatsuki Koike / Yuhei Miyanohana / Yuji Shimizu / Rameshu Rallabandi / Peng Lian / ...Authors: Jie Yin / Yanyong Kang / Aaron P McGrath / Karen Chapman / Megan Sjodt / Eiji Kimura / Atsutoshi Okabe / Tatsuki Koike / Yuhei Miyanohana / Yuji Shimizu / Rameshu Rallabandi / Peng Lian / Xiaochen Bai / Mack Flinspach / Jef K De Brabander / Daniel M Rosenbaum / Abstract: The OX orexin receptor (OXR) is a highly expressed G protein-coupled receptor (GPCR) in the brain that regulates wakefulness and circadian rhythms in humans. Antagonism of OXR is a proven therapeutic ...The OX orexin receptor (OXR) is a highly expressed G protein-coupled receptor (GPCR) in the brain that regulates wakefulness and circadian rhythms in humans. Antagonism of OXR is a proven therapeutic strategy for insomnia drugs, and agonism of OXR is a potentially powerful approach for narcolepsy type 1, which is characterized by the death of orexinergic neurons. Until recently, agonism of OXR had been considered 'undruggable.' We harness cryo-electron microscopy of OXR-G protein complexes to determine how the first clinically tested OXR agonist TAK-925 can activate OXR in a highly selective manner. Two structures of TAK-925-bound OXR with either a G mimetic or G reveal that TAK-925 binds at the same site occupied by antagonists, yet interacts with the transmembrane helices to trigger activating microswitches. Our structural and mutagenesis data show that TAK-925's selectivity is mediated by subtle differences between OX and OX receptor subtypes at the orthosteric pocket. Finally, differences in the polarity of interactions at the G protein binding interfaces help to rationalize OXR's coupling selectivity for G signaling. The mechanisms of TAK-925's binding, activation, and selectivity presented herein will aid in understanding the efficacy of small molecule OXR agonists for narcolepsy and other circadian disorders. | |||||||||
History |
|
-Structure visualization
Supplemental images |
---|
-Downloads & links
-EMDB archive
Map data | emd_25389.map.gz | 49.7 MB | EMDB map data format | |
---|---|---|---|---|
Header (meta data) | emd-25389-v30.xml emd-25389.xml | 20.3 KB 20.3 KB | Display Display | EMDB header |
FSC (resolution estimation) | emd_25389_fsc.xml | 11.7 KB | Display | FSC data file |
Images | emd_25389.png | 51.4 KB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-25389 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-25389 | HTTPS FTP |
-Validation report
Summary document | emd_25389_validation.pdf.gz | 441.6 KB | Display | EMDB validaton report |
---|---|---|---|---|
Full document | emd_25389_full_validation.pdf.gz | 441.2 KB | Display | |
Data in XML | emd_25389_validation.xml.gz | 10.9 KB | Display | |
Data in CIF | emd_25389_validation.cif.gz | 14.2 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-25389 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-25389 | HTTPS FTP |
-Related structure data
Related structure data | 7sqoMC 7sr8C M: atomic model generated by this map C: citing same article (ref.) |
---|---|
Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
---|---|
Related items in Molecule of the Month |
-Map
File | Download / File: emd_25389.map.gz / Format: CCP4 / Size: 52.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Annotation | Orexin-2 receptor (OX2R) bound to TAK-925, Gi and scFv16 | ||||||||||||||||||||
Voxel size | X=Y=Z: 1.04 Å | ||||||||||||||||||||
Density |
| ||||||||||||||||||||
Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
|
-Supplemental data
-Sample components
+Entire : Human OX2R in complex with Gai/Gb/Gg-scFv16.
+Supramolecule #1: Human OX2R in complex with Gai/Gb/Gg-scFv16.
+Supramolecule #2: Orexin receptor type 2
+Supramolecule #3: Guanine nucleotide-binding protein G(i) subunit alpha-1
+Supramolecule #4: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1,...
+Supramolecule #5: scFv-16
+Macromolecule #1: Orexin receptor type 2
+Macromolecule #2: 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 #4: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
+Macromolecule #5: scFv-16
+Macromolecule #6: OLEIC ACID
+Macromolecule #7: methyl (2R,3S)-3-[(methanesulfonyl)amino]-2-({[(1s,4S)-4-phenylcy...
-Experimental details
-Structure determination
Method | cryo EM |
---|---|
Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Concentration | 5 mg/mL |
---|---|
Buffer | pH: 7.2 |
Vitrification | Cryogen name: ETHANE |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
---|---|
Specialist optics | Energy filter - Name: GIF Bioquantum |
Image recording | Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 43.7 e/Å2 Details: Cryo-EM movie stacks were collected on a Titan Krios microscope operated at 300 kV under EFTEM mode. Nanoprobe with 1um illumination area was used. Data were recorded on a postGIF Gatan K2 ...Details: Cryo-EM movie stacks were collected on a Titan Krios microscope operated at 300 kV under EFTEM mode. Nanoprobe with 1um illumination area was used. Data were recorded on a postGIF Gatan K2 summit camera at a nominal magnification of 130,000, using super-resolution counting model. Bioquantum energy filter was operated in the zero-energy-loss mode with an energy slit width of 20 eV. |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal magnification: 130000 |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
+Image processing
-Atomic model buiding 1
Refinement | Protocol: RIGID BODY FIT |
---|---|
Output model | PDB-7sqo: |