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- EMDB-33247: Cryo-EM structure of the Neuromedin U receptor 2 (NMUR2) in compl... -

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Entry
Database: EMDB / ID: EMD-33247
TitleCryo-EM structure of the Neuromedin U receptor 2 (NMUR2) in complex with G Protein and its endogeneous Peptide-Agonist NMU25
Map data
Sample
  • Complex: NmU25-NMU2-Gi1 complex
    • Protein or peptide: Neuromedin-U-25
    • Protein or peptide: Neuromedin-U receptor 2
    • Protein or peptide: Guanine nucleotide-binding protein G(i) subunit alpha-1
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
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 / 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 / temperature homeostasis / arachidonic acid secretion / response to pain / neuropeptide signaling pathway / Adenylate cyclase inhibitory pathway / positive regulation of protein localization to cell cortex / regulation of cAMP-mediated signaling / positive regulation of synaptic transmission / 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 activity / G protein-coupled receptor binding / 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 / Prostacyclin signalling through prostacyclin receptor / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / terminal bouton / 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 / response to peptide hormone / 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 / GDP binding / calcium ion transport / 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) / retina development in camera-type eye / GTPase binding / cell-cell signaling / phospholipase C-activating G protein-coupled receptor signaling pathway / Ca2+ pathway / cell cortex / midbody / G alpha (i) signalling events / positive regulation of cytosolic calcium ion concentration / fibroblast proliferation / G alpha (s) signalling events / G alpha (q) signalling events / cell population proliferation / Ras protein signal transduction / Extra-nuclear estrogen signaling / G protein-coupled receptor signaling pathway / cell cycle / lysosomal membrane / cell division / signaling receptor binding
Similarity search - Function
Neuromedin U receptor / Neuromedin U receptor, type 2 / Neuromedin-U receptor 2, C-terminal domain / Neuromedin-U receptor 2, C-terminal / Neuromedin U, C-terminal / Neuromedin-U / Neuromedin U / Neuromedin U / Neuromedin U, amidation site / Neuromedin U signature. ...Neuromedin U receptor / Neuromedin U receptor, type 2 / Neuromedin-U receptor 2, C-terminal domain / Neuromedin-U receptor 2, C-terminal / Neuromedin U, C-terminal / Neuromedin-U / Neuromedin U / Neuromedin U / Neuromedin U, amidation site / Neuromedin U signature. / G-protein alpha subunit, group I / Serpentine type 7TM GPCR chemoreceptor Srsx / G-alpha domain profile. / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G protein alpha subunit / G-protein, gamma subunit / G-protein gamma subunit domain profile. / GGL domain / G-protein gamma-like domain superfamily / G-protein gamma-like domain / GGL domain / G protein gamma subunit-like motifs / Guanine nucleotide-binding protein, beta subunit / G-protein, beta subunit / G-protein coupled receptors family 1 signature. / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. / 7 transmembrane receptor (rhodopsin family) / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD domain, G-beta repeat / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Neuromedin-U / Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Guanine nucleotide-binding protein G(i) subunit alpha-1 / Neuromedin-U receptor 2
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsZhao 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, 1 items
OrganizationGrant numberCountry
National Science Foundation (NSF, China)31825010 China
CitationJournal: 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
DepositionApr 19, 2022-
Header (metadata) releaseFeb 22, 2023-
Map releaseFeb 22, 2023-
UpdateFeb 22, 2023-
Current statusFeb 22, 2023Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_33247.png

Downloads & links

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Map

FileDownload / File: emd_33247.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.045 Å
Density
Contour LevelBy AUTHOR: 0.022
Minimum - Maximum-0.11355607 - 0.18658137
Average (Standard dev.)-2.4859544e-05 (±0.0031336863)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 267.52 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_33247_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_33247_half_map_2.map
Projections & Slices
AxesZYX

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Histogram

Histogram (log scale)

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Sample components

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Entire : NmU25-NMU2-Gi1 complex

EntireName: NmU25-NMU2-Gi1 complex
Components
  • Complex: NmU25-NMU2-Gi1 complex
    • Protein or peptide: Neuromedin-U-25
    • Protein or peptide: Neuromedin-U receptor 2
    • Protein or peptide: Guanine nucleotide-binding protein G(i) subunit alpha-1
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2

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Supramolecule #1: NmU25-NMU2-Gi1 complex

SupramoleculeName: NmU25-NMU2-Gi1 complex / type: complex / ID: 1 / Chimera: Yes / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Neuromedin-U-25

MacromoleculeName: Neuromedin-U-25 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 3.083398 KDa
SequenceString:
FRVDEEFQSP FASQSRGYFL FRPRN(NH2)

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Macromolecule #2: Neuromedin-U receptor 2

MacromoleculeName: Neuromedin-U receptor 2 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 44.701961 KDa
Recombinant expressionOrganism: Insecta environmental sample (insect)
SequenceString: 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

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Macromolecule #3: Guanine nucleotide-binding protein G(i) subunit alpha-1

MacromoleculeName: Guanine nucleotide-binding protein G(i) subunit alpha-1
type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 40.447141 KDa
Recombinant expressionOrganism: Insecta environmental sample (insect)
SequenceString: 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

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Macromolecule #4: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1

MacromoleculeName: 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
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 38.744371 KDa
Recombinant expressionOrganism: Insecta environmental sample (insect)
SequenceString: 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

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Macromolecule #5: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2

MacromoleculeName: 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
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 7.861143 KDa
Recombinant expressionOrganism: Insecta environmental sample (insect)
SequenceString:
MASNNTASIA QARKLVEQLK MEANIDRIKV SKAAADLMAY CEAHAKEDPL LTPVPASENP FREKKFFCAI L

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.5
Component:
ConcentrationFormulaName
25.0 mMHEPES4- (2-hydroxyethyl)-1-piperazineethanesulfonic acid
150.0 mMNaClSodium chloridesodium chloride
0.002 mg/mlLMNGLauryl Maltose Neopentyl Glycol
0.0002 mg/mlCHSCholesteryl hemisuccinate
GridMaterial: NICKEL/TITANIUM
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 1.5 µm / Nominal defocus min: 0.8 µm
Sample stageCooling holder cryogen: NITROGEN
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 70.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 912031

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