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Yorodumi- PDB-7l1v: Orexin Receptor 2 (OX2R) in Complex with G Protein and Small-Mole... -
+Open data
-Basic information
Entry | Database: PDB / ID: 7l1v | ||||||
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Title | Orexin Receptor 2 (OX2R) in Complex with G Protein and Small-Molecule Agonist Compound 1 | ||||||
Components |
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Keywords | MEMBRANE PROTEIN / Class A GPCR / Orexin receptor 2 / OX2R / Peptide agonist | ||||||
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 / feeding behavior / locomotion / peptide hormone binding / neuropeptide signaling pathway / cellular response to hormone stimulus ...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 / feeding behavior / locomotion / peptide hormone binding / neuropeptide signaling pathway / cellular response to hormone stimulus / regulation of cytosolic calcium ion concentration / peptide 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 / G protein-coupled acetylcholine receptor signaling pathway / 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 / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / ADP signalling through P2Y purinoceptor 12 / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / Sensory perception of sweet, bitter, and umami (glutamate) taste / 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 / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / sensory perception of taste / ADP signalling through P2Y purinoceptor 1 / adenylate cyclase-activating dopamine receptor signaling pathway / G beta:gamma signalling through PI3Kgamma / cellular response to prostaglandin E stimulus / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / GPER1 signaling / G-protein beta-subunit binding / Inactivation, recovery and regulation of the phototransduction cascade / heterotrimeric G-protein complex / G alpha (12/13) signalling events / extracellular vesicle / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / GTPase binding / retina development in camera-type eye / Ca2+ pathway / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (i) signalling events / fibroblast proliferation / G alpha (s) signalling events / Ras protein signal transduction / G alpha (q) signalling events / chemical synaptic transmission / Extra-nuclear estrogen signaling / cell population proliferation / G protein-coupled receptor signaling pathway / lysosomal membrane / GTPase activity / synapse / protein-containing complex binding / signal transduction / extracellular exosome / membrane / plasma membrane / cytoplasm / cytosol Similarity search - Function | ||||||
Biological species | Homo sapiens (human) Mus musculus (house mouse) Lama glama (llama) | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3 Å | ||||||
Authors | Hong, C. / Byrne, N.J. / Zamlynny, B. / Tummala, S. / Xiao, L. / Shipman, J.M. / Partridge, A.T. / Minnick, C. / Breslin, M.J. / Rudd, M.T. ...Hong, C. / Byrne, N.J. / Zamlynny, B. / Tummala, S. / Xiao, L. / Shipman, J.M. / Partridge, A.T. / Minnick, C. / Breslin, M.J. / Rudd, M.T. / Stachel, S.J. / Rada, V.L. / Kern, J.C. / Armacost, K.A. / Hollingsworth, S.A. / O'Brien, J.A. / Hall, D.L. / McDonald, T.P. / Strickland, C. / Brooun, A. / Soisson, S.M. / Hollenstein, K. | ||||||
Citation | Journal: Nat Commun / Year: 2021 Title: Structures of active-state orexin receptor 2 rationalize peptide and small-molecule agonist recognition and receptor activation. Authors: Chuan Hong / Noel J Byrne / Beata Zamlynny / Srivanya Tummala / Li Xiao / Jennifer M Shipman / Andrea T Partridge / Christina Minnick / Michael J Breslin / Michael T Rudd / Shawn J Stachel / ...Authors: Chuan Hong / Noel J Byrne / Beata Zamlynny / Srivanya Tummala / Li Xiao / Jennifer M Shipman / Andrea T Partridge / Christina Minnick / Michael J Breslin / Michael T Rudd / Shawn J Stachel / Vanessa L Rada / Jeffrey C Kern / Kira A Armacost / Scott A Hollingsworth / Julie A O'Brien / Dawn L Hall / Terrence P McDonald / Corey Strickland / Alexei Brooun / Stephen M Soisson / Kaspar Hollenstein / Abstract: Narcolepsy type 1 (NT1) is a chronic neurological disorder that impairs the brain's ability to control sleep-wake cycles. Current therapies are limited to the management of symptoms with modest ...Narcolepsy type 1 (NT1) is a chronic neurological disorder that impairs the brain's ability to control sleep-wake cycles. Current therapies are limited to the management of symptoms with modest effectiveness and substantial adverse effects. Agonists of the orexin receptor 2 (OXR) have shown promise as novel therapeutics that directly target the pathophysiology of the disease. However, identification of drug-like OXR agonists has proven difficult. Here we report cryo-electron microscopy structures of active-state OXR bound to an endogenous peptide agonist and a small-molecule agonist. The extended carboxy-terminal segment of the peptide reaches into the core of OXR to stabilize an active conformation, while the small-molecule agonist binds deep inside the orthosteric pocket, making similar key interactions. Comparison with antagonist-bound OXR suggests a molecular mechanism that rationalizes both receptor activation and inhibition. Our results enable structure-based discovery of therapeutic orexin agonists for the treatment of NT1 and other hypersomnia disorders. | ||||||
History |
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-Structure visualization
Movie |
Movie viewer |
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Structure viewer | Molecule: MolmilJmol/JSmol |
-Downloads & links
-Download
PDBx/mmCIF format | 7l1v.cif.gz | 230.9 KB | Display | PDBx/mmCIF format |
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PDB format | pdb7l1v.ent.gz | 181.2 KB | Display | PDB format |
PDBx/mmJSON format | 7l1v.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/l1/7l1v ftp://data.pdbj.org/pub/pdb/validation_reports/l1/7l1v | HTTPS FTP |
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-Related structure data
Related structure data | 23119MC 7l1uC M: map data used to model this data C: citing same article (ref.) |
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Similar structure data |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
-Protein , 2 types, 2 molecules AR
#1: Protein | Mass: 28040.881 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli (E. coli) |
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#5: Protein | Mass: 43470.875 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: HCRTR2 / Production host: Homo sapiens (human) / References: UniProt: Q548Y0, UniProt: O43614*PLUS |
-Guanine nucleotide-binding protein ... , 2 types, 2 molecules BC
#2: Protein | Mass: 38579.148 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: GNB1 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P62873 |
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#3: Protein | Mass: 7845.078 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: GNG2 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P59768 |
-Antibody , 2 types, 2 molecules HS
#4: Antibody | Mass: 26610.615 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Mus musculus (house mouse) / Production host: Escherichia coli (E. coli) |
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#6: Antibody | Mass: 12786.225 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Lama glama (llama) / Production host: Escherichia coli (E. coli) |
-Non-polymers , 1 types, 1 molecules
#7: Chemical | ChemComp-XGD / |
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-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: Orexin Receptor 2 (OX2R) in Complex with G Protein and Small-Molecule Agonist Compound 1 Type: COMPLEX / Entity ID: #1-#6 / Source: MULTIPLE SOURCES | ||||||||||||||||||||||||||||||
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Molecular weight | Experimental value: NO | ||||||||||||||||||||||||||||||
Source (natural) |
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Source (recombinant) |
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Buffer solution | pH: 7.6 | ||||||||||||||||||||||||||||||
Buffer component |
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Specimen | Conc.: 5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES | ||||||||||||||||||||||||||||||
Specimen support | Details: Carbon side facing up / Grid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: C-flat-1.2/1.3 | ||||||||||||||||||||||||||||||
Vitrification | Instrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 95 % / Chamber temperature: 277 K / Details: 3s blot from both sides |
-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 FIELD / Nominal magnification: 105000 X / Calibrated magnification: 59524 X / Nominal defocus max: 1800 nm / Nominal defocus min: 800 nm / Calibrated defocus min: 600 nm / Calibrated defocus max: 2200 nm / Cs: 2.7 mm / C2 aperture diameter: 50 µm / Alignment procedure: BASIC |
Specimen holder | Cryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Temperature (max): 93 K / Temperature (min): 83 K |
Image recording | Average exposure time: 0.05 sec. / Electron dose: 1.0625 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) / Num. of grids imaged: 2 / Num. of real images: 18000 / Details: 40 frames with total 2s exposure per movie |
EM imaging optics | Energyfilter name: GIF Bioquantum / Energyfilter slit width: 20 eV |
Image scans | Sampling size: 5 µm / Width: 5700 / Height: 4100 |
-Processing
EM software |
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||||||||||||||||||||||||||||
Particle selection | Num. of particles selected: 7500000 | ||||||||||||||||||||||||||||||||||||||||||||||||||
Symmetry | Point symmetry: C1 (asymmetric) | ||||||||||||||||||||||||||||||||||||||||||||||||||
3D reconstruction | Resolution: 3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 1100000 / Algorithm: FOURIER SPACE / Details: Gold standard with masking effect correction / Num. of class averages: 1 / Symmetry type: POINT | ||||||||||||||||||||||||||||||||||||||||||||||||||
Atomic model building |
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Atomic model building |
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