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- EMDB-33247: Cryo-EM structure of the Neuromedin U receptor 2 (NMUR2) in compl... -
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Open data
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Basic information
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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 | |||||||||
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Function / homology | ![]() 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 / intracellularly calcium-gated chloride channel activity / regulation of feeding behavior ...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 / intracellularly calcium-gated chloride channel activity / regulation of feeding behavior / regulation of grooming behavior / regulation of smooth muscle contraction / regulation of sensory perception of pain / grooming behavior / positive regulation of smooth muscle contraction / feeding behavior / arachidonic acid secretion / temperature homeostasis / response to pain / Adenylate cyclase inhibitory pathway / neuropeptide signaling 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 / 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 / G-protein beta/gamma-subunit complex binding / Olfactory Signaling Pathway / Activation of the phototransduction cascade / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / G-protein activation / G protein-coupled acetylcholine receptor signaling pathway / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / terminal bouton / 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 / response to peptide hormone / 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 / calcium ion transport / GPER1 signaling / GDP binding / 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 / cell-cell signaling / retina development in camera-type eye / phospholipase C-activating G protein-coupled receptor signaling pathway / Ca2+ pathway / cell cortex / midbody / positive regulation of cytosolic calcium ion concentration / G alpha (i) signalling events / fibroblast proliferation / G alpha (s) signalling events / G alpha (q) signalling events / cell population proliferation / Ras protein signal transduction / Extra-nuclear estrogen signaling / cell cycle / G protein-coupled receptor signaling pathway / cell division / lysosomal membrane / signaling receptor binding Similarity search - Function | |||||||||
Biological species | ![]() | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.3 Å | |||||||||
![]() | 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 | ![]()
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![]() | ![]() 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
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 59.9 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 19.7 KB 19.7 KB | Display Display | ![]() |
Images | ![]() | 26.9 KB | ||
Others | ![]() ![]() | 49.7 MB 49.7 MB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Validation report
Summary document | ![]() | 642.8 KB | Display | ![]() |
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Full document | ![]() | 642.4 KB | Display | |
Data in XML | ![]() | 12 KB | Display | |
Data in CIF | ![]() | 14.1 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 7xk8MC M: atomic model generated by this map C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
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Voxel size | X=Y=Z: 1.045 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Half map: #2
File | emd_33247_half_map_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #1
File | emd_33247_half_map_2.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
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Sample components
-Entire : NmU25-NMU2-Gi1 complex
Entire | Name: NmU25-NMU2-Gi1 complex |
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Components |
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-Supramolecule #1: NmU25-NMU2-Gi1 complex
Supramolecule | Name: NmU25-NMU2-Gi1 complex / type: complex / ID: 1 / Chimera: Yes / Parent: 0 / Macromolecule list: all |
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Source (natural) | Organism: ![]() |
-Macromolecule #1: Neuromedin-U-25
Macromolecule | Name: Neuromedin-U-25 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 3.083398 KDa |
Sequence | String: FRVDEEFQSP FASQSRGYFL FRPRN(NH2) |
-Macromolecule #2: Neuromedin-U receptor 2
Macromolecule | Name: Neuromedin-U receptor 2 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 44.701961 KDa |
Recombinant expression | Organism: ![]() |
Sequence | String: DYKDDDDGAP MSGMEKLQNA SWIYQQKLED PFQKHLNSTE EYLAFLCGPR RSHFFLPVSV VYVPIFVVGV IGNVLVCLVI LQHQAMKTP TNYYLFSLAV SDLLVLLLGM PLEVYEMWRN YPFLFGPVGC YFKTALFETV CFASILSITT VSVERYVAIL H PFRAKLQS ...String: DYKDDDDGAP MSGMEKLQNA SWIYQQKLED PFQKHLNSTE EYLAFLCGPR RSHFFLPVSV VYVPIFVVGV IGNVLVCLVI LQHQAMKTP TNYYLFSLAV SDLLVLLLGM PLEVYEMWRN YPFLFGPVGC YFKTALFETV CFASILSITT VSVERYVAIL H PFRAKLQS TRRRALRILG IVWGFSVLFS LPNTSIHGIK FHYFPNGSLV PGSATCTVIK PMWIYNFIIQ VTSFLFYLLP MT VISVLYY LMALRLKKDK SLEADEGNAN IQRPCRKSVN KMLFVLVLVF AICWAPFHID RLFFSFVEEW SESLAAVFNL VHV VSGVFF YLSSAVNPII YNLLSRRFQA AFQNVISSFE FLEVLFQGPW SHPQFEKGGG SGGGSGGSAW SHPQFEK |
-Macromolecule #3: Guanine nucleotide-binding protein G(i) subunit alpha-1
Macromolecule | Name: Guanine nucleotide-binding protein G(i) subunit alpha-1 type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 40.447141 KDa |
Recombinant expression | Organism: ![]() |
Sequence | String: MGCTLSAEDK AAVERSKMID RNLREDGEKA AREVKLLLLG AGESGKCTIV KQMKIIHEAG YSEEECKQYK AVVYSNTIQS IIAIIRAMG RLKIDFGDSA RADDARQLFV LAGAAEEGFM TAELAGVIKR LWKDSGVQAC FNRSREYQLN DSAAYYLNDL D RIAQPNYI ...String: MGCTLSAEDK AAVERSKMID RNLREDGEKA AREVKLLLLG AGESGKCTIV KQMKIIHEAG YSEEECKQYK AVVYSNTIQS IIAIIRAMG RLKIDFGDSA RADDARQLFV LAGAAEEGFM TAELAGVIKR LWKDSGVQAC FNRSREYQLN DSAAYYLNDL D RIAQPNYI PTQQDVLRTR VKTTGIVETH FTFKDLHFKM FDVTAQRSER KKWIHCFEGV TAIIFCVALS DYDLVLAEDE EM NRMHASM KLFDSICNNK WFTDTSIILF LNKKDLFEEK IKKSPLTICY PEYAGSNTYE EAAAYIQCQF EDLNKRKDTK EIY THFTCS TDTKNVQFVF DAVTDVIIKN NLKDCGLF |
-Macromolecule #4: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
Macromolecule | Name: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 38.744371 KDa |
Recombinant expression | Organism: ![]() |
Sequence | String: MHHHHHHGSL LQSELDQLRQ EAEQLKNQIR DARKACADAT LSQITNNIDP VGRIQMRTRR TLRGHLAKIY AMHWGTDSRL LVSASQDGK LIIWDSYTTN KVHAIPLRSS WVMTCAYAPS GNYVACGGLD NICSIYNLKT REGNVRVSRE LAGHTGYLSC C RFLDDNQI ...String: MHHHHHHGSL LQSELDQLRQ EAEQLKNQIR DARKACADAT LSQITNNIDP VGRIQMRTRR TLRGHLAKIY AMHWGTDSRL LVSASQDGK LIIWDSYTTN KVHAIPLRSS WVMTCAYAPS GNYVACGGLD NICSIYNLKT REGNVRVSRE LAGHTGYLSC C RFLDDNQI VTSSGDTTCA LWDIETGQQT TTFTGHTGDV MSLSLAPDTR LFVSGACDAS AKLWDVREGM CRQTFTGHES DI NAICFFP NGNAFATGSD DATCRLFDLR ADQELMTYSH DNIICGITSV SFSKSGRLLL AGYDDFNCNV WDALKADRAG VLA GHDNRV SCLGVTDDGM AVATGSWDSF LKIWN |
-Macromolecule #5: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
Macromolecule | Name: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 7.861143 KDa |
Recombinant expression | Organism: ![]() |
Sequence | String: MASNNTASIA QARKLVEQLK MEANIDRIKV SKAAADLMAY CEAHAKEDPL LTPVPASENP FREKKFFCAI L |
-Experimental details
-Structure determination
Method | cryo EM |
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![]() | single particle reconstruction |
Aggregation state | particle |
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Sample preparation
Buffer | pH: 7.5 Component:
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Grid | Material: NICKEL/TITANIUM | |||||||||||||||
Vitrification | Cryogen name: ETHANE |
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Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 70.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.5 µm / Nominal defocus min: 0.8 µm |
Sample stage | Cooling holder cryogen: NITROGEN |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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Image processing
Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 912031 |
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Initial angle assignment | Type: MAXIMUM LIKELIHOOD |
Final angle assignment | Type: MAXIMUM LIKELIHOOD |