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Yorodumi- PDB-7xk8: Cryo-EM structure of the Neuromedin U receptor 2 (NMUR2) in compl... -
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-Basic information
Entry | Database: PDB / ID: 7xk8 | ||||||
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Title | Cryo-EM structure of the Neuromedin U receptor 2 (NMUR2) in complex with G Protein and its endogeneous Peptide-Agonist NMU25 | ||||||
Components |
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Keywords | MEMBRANE PROTEIN / GPCR / complex | ||||||
Function / homology | Function and homology information neuromedin U receptor activity / neuromedin U binding / type 1 neuromedin U receptor binding / type 2 neuromedin U receptor binding / neuromedin U receptor binding / : / reduction of food intake in response to dietary excess / neuropeptide receptor activity / regulation of feeding behavior / intracellularly calcium-gated chloride channel activity ...neuromedin U receptor activity / neuromedin U binding / type 1 neuromedin U receptor binding / type 2 neuromedin U receptor binding / neuromedin U receptor binding / : / reduction of food intake in response to dietary excess / neuropeptide receptor activity / regulation of feeding behavior / intracellularly calcium-gated chloride channel activity / regulation of grooming behavior / regulation of sensory perception of pain / regulation of smooth muscle contraction / grooming behavior / positive regulation of smooth muscle contraction / feeding behavior / arachidonate secretion / temperature homeostasis / response to pain / neuropeptide signaling pathway / T cell migration / Adenylate cyclase inhibitory pathway / positive regulation of protein localization to cell cortex / positive regulation of synaptic transmission / regulation of cAMP-mediated signaling / D2 dopamine receptor binding / G protein-coupled serotonin receptor binding / energy homeostasis / regulation of mitotic spindle organization / cellular response to forskolin / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / G-protein beta/gamma-subunit complex binding / Peptide ligand-binding receptors / central nervous system development / Regulation of insulin secretion / G protein-coupled receptor binding / G protein-coupled receptor activity / calcium-mediated signaling / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / Olfactory Signaling Pathway / Activation of the phototransduction cascade / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / terminal bouton / Glucagon signaling in metabolic regulation / 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 / G beta:gamma signalling through CDC42 / response to peptide hormone / Vasopressin regulates renal water homeostasis via Aquaporins / G beta:gamma signalling through BTK / ADP signalling through P2Y purinoceptor 12 / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / Glucagon-type ligand receptors / Sensory perception of sweet, bitter, and umami (glutamate) taste / photoreceptor disc membrane / G alpha (z) signalling events / Adrenaline,noradrenaline inhibits insulin secretion / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / cellular response to catecholamine stimulus / sensory perception of taste / ADP signalling through P2Y purinoceptor 1 / adenylate cyclase-activating dopamine receptor signaling pathway / G beta:gamma signalling through PI3Kgamma / GPER1 signaling / cellular response to prostaglandin E stimulus / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / calcium ion transport / GDP binding / Inactivation, recovery and regulation of the phototransduction cascade / G-protein beta-subunit binding / heterotrimeric G-protein complex / Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement / G alpha (12/13) signalling events / extracellular vesicle / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / cell-cell signaling / GTPase binding / retina development in camera-type eye / Ca2+ pathway / phospholipase C-activating G protein-coupled receptor signaling pathway / positive regulation of cytosolic calcium ion concentration / cell cortex / midbody / G alpha (i) signalling events / fibroblast proliferation / G alpha (s) signalling events / G alpha (q) signalling events / Ras protein signal transduction / cell population proliferation / Extra-nuclear estrogen signaling / G protein-coupled receptor signaling pathway / lysosomal membrane / cell division Similarity search - Function | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.3 Å | ||||||
Authors | Zhao, W. / Wenru, Z. / Mu, W. / Minmin, L. / Shutian, C. / Tingting, T. / Gisela, S. / Holger, W. / Albert, B. / Cuiying, Y. ...Zhao, W. / Wenru, Z. / Mu, W. / Minmin, L. / Shutian, C. / Tingting, T. / Gisela, S. / Holger, W. / Albert, B. / Cuiying, Y. / Xiaojing, C. / Han, S. / Wu, B. / Zhao, Q. | ||||||
Funding support | China, 1items
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Citation | Journal: Nat Commun / Year: 2022 Title: Ligand recognition and activation of neuromedin U receptor 2. Authors: Wenli Zhao / Wenru Zhang / Mu Wang / Minmin Lu / Shutian Chen / Tingting Tang / Gisela Schnapp / Holger Wagner / Albert Brennauer / Cuiying Yi / Xiaojing Chu / Shuo Han / Beili Wu / Qiang Zhao / Abstract: Neuromedin U receptor 2 (NMU2), an emerging attractive target for treating obesity, has shown the capability in reducing food intake and regulating energy metabolism when activated. However, drug ...Neuromedin U receptor 2 (NMU2), an emerging attractive target for treating obesity, has shown the capability in reducing food intake and regulating energy metabolism when activated. However, drug development of NMU2 was deferred partially due to the lack of structural information. Here, we present the cryo-electron microscopy (cryo-EM) structure of NMU2 bound to the endogenous agonist NmU-25 and G at 3.3 Å resolution. Combined with functional and computational data, the structure reveals the key factors that govern the recognition and selectivity of peptide agonist as well as non-peptide antagonist, providing the structural basis for design of novel and highly selective drugs targeting NMU2. In addition, a 25-degree rotation of G protein in reference to NMU2 is also observed compared in other structures of class A GPCR-G complexes, suggesting heterogeneity in the processes of G protein-coupled receptors (GPCRs) activation and G protein coupling. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 7xk8.cif.gz | 170.9 KB | Display | PDBx/mmCIF format |
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PDB format | pdb7xk8.ent.gz | 129 KB | Display | PDB format |
PDBx/mmJSON format | 7xk8.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 7xk8_validation.pdf.gz | 1006.7 KB | Display | wwPDB validaton report |
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Full document | 7xk8_full_validation.pdf.gz | 1014.3 KB | Display | |
Data in XML | 7xk8_validation.xml.gz | 35.8 KB | Display | |
Data in CIF | 7xk8_validation.cif.gz | 51.8 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/xk/7xk8 ftp://data.pdbj.org/pub/pdb/validation_reports/xk/7xk8 | HTTPS FTP |
-Related structure data
Related structure data | 33247MC M: map data used to model this data C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
#1: Protein/peptide | Mass: 3083.398 Da / Num. of mol.: 1 / Source method: obtained synthetically / Details: C-terminal amidation / Source: (synth.) Homo sapiens (human) / References: UniProt: P48645 |
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#2: Protein | Mass: 44701.961 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: NMUR2, NMU2R, TGR1 / Production host: Insecta environmental sample (insect) / References: UniProt: Q9GZQ4 |
#3: Protein | Mass: 40447.141 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: GNAI1 / Production host: Insecta environmental sample (insect) / References: UniProt: P63096 |
#4: Protein | Mass: 38744.371 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: GNB1 / Production host: Insecta environmental sample (insect) / References: UniProt: P62873 |
#5: Protein | Mass: 7861.143 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: GNG2 / Production host: Insecta environmental sample (insect) / References: UniProt: P59768 |
Has ligand of interest | N |
-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: NmU25-NMU2-Gi1 complex / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT | |||||||||||||||||||||||||
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Molecular weight | Experimental value: NO | |||||||||||||||||||||||||
Source (natural) | Organism: Homo sapiens (human) | |||||||||||||||||||||||||
Source (recombinant) | Organism: Insecta environmental sample (insect) | |||||||||||||||||||||||||
Buffer solution | pH: 7.5 | |||||||||||||||||||||||||
Buffer component |
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Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES | |||||||||||||||||||||||||
Specimen support | Grid material: NICKEL/TITANIUM | |||||||||||||||||||||||||
Vitrification | Cryogen name: ETHANE |
-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 defocus max: 1500 nm / Nominal defocus min: 800 nm |
Specimen holder | Cryogen: NITROGEN |
Image recording | Electron dose: 70 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) |
-Processing
Software | Name: PHENIX / Version: 1.15.2_3472: / Classification: refinement | ||||||||||||||||||||||||
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EM software | Name: SerialEM / Version: 3.7 / Category: image acquisition | ||||||||||||||||||||||||
CTF correction | Type: NONE | ||||||||||||||||||||||||
3D reconstruction | Resolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 912031 / Symmetry type: POINT | ||||||||||||||||||||||||
Refinement | Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2 | ||||||||||||||||||||||||
Displacement parameters | Biso mean: 71.4 Å2 | ||||||||||||||||||||||||
Refine LS restraints |
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