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- 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
TitleCryo-EM structure of the Neuromedin U receptor 2 (NMUR2) in complex with G Protein and its endogeneous Peptide-Agonist NMU25
Components
  • 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
  • Neuromedin-U-25
KeywordsMEMBRANE 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 grooming behavior / 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 / regulation of grooming behavior / intracellularly calcium-gated chloride channel activity / regulation of feeding behavior / grooming behavior / positive regulation of smooth muscle contraction / regulation of smooth muscle contraction / feeding behavior / arachidonate secretion / response to pain / temperature homeostasis / neuropeptide signaling pathway / positive regulation of synaptic transmission / positive regulation of protein localization to cell cortex / Adenylate cyclase inhibitory pathway / T cell migration / energy homeostasis / D2 dopamine receptor binding / response to prostaglandin E / G protein-coupled serotonin receptor binding / adenylate cyclase regulator activity / adenylate cyclase-inhibiting serotonin receptor signaling pathway / cellular response to forskolin / regulation of mitotic spindle organization / positive regulation of calcium-mediated signaling / Peptide ligand-binding receptors / central nervous system development / Regulation of insulin secretion / positive regulation of cholesterol biosynthetic process / G protein-coupled receptor binding / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / terminal bouton / G protein-coupled receptor activity / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / response to peptide hormone / G-protein beta/gamma-subunit complex binding / centriolar satellite / 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 / G beta:gamma signalling through CDC42 / Glucagon signaling in metabolic regulation / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / ADP signalling through P2Y purinoceptor 12 / Sensory perception of sweet, bitter, and umami (glutamate) taste / photoreceptor disc membrane / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / GDP binding / G alpha (z) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / cellular response to catecholamine stimulus / ADORA2B mediated anti-inflammatory cytokines production / ADP signalling through P2Y purinoceptor 1 / G beta:gamma signalling through PI3Kgamma / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / adenylate cyclase-activating dopamine receptor signaling pathway / GPER1 signaling / Inactivation, recovery and regulation of the phototransduction cascade / cellular response to prostaglandin E stimulus / G-protein beta-subunit binding / heterotrimeric G-protein complex / G alpha (12/13) signalling events / sensory perception of taste / cell-cell signaling / extracellular vesicle / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / G protein activity / GTPase binding / Ca2+ pathway / retina development in camera-type eye / midbody / cell cortex / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / fibroblast proliferation / G alpha (i) signalling events / Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement / G alpha (s) signalling events / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (q) signalling events / Ras protein signal transduction / Extra-nuclear estrogen signaling / cell population proliferation / ciliary basal body
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 / YVTN repeat-like/Quinoprotein amine dehydrogenase / Serpentine type 7TM GPCR chemoreceptor Srsx / 7 Propeller / Methylamine Dehydrogenase; Chain H / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G-alpha domain profile. / G protein alpha subunit / G-protein, gamma subunit / G-protein gamma subunit domain profile. / G-protein gamma-like domain / G-protein gamma-like domain superfamily / GGL domain / G protein gamma subunit-like motifs / GGL domain / 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. / WD domain, G-beta repeat / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / P-loop containing nucleoside triphosphate hydrolase / Mainly Beta
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)
MethodELECTRON MICROSCOPY / single 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, 1items
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, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Feb 22, 2023Provider: repository / Type: Initial release
Revision 1.1Nov 13, 2024Group: Data collection / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
P: Neuromedin-U-25
R: Neuromedin-U receptor 2
A: Guanine nucleotide-binding protein G(i) subunit alpha-1
B: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
C: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2


Theoretical massNumber of molelcules
Total (without water)134,8385
Polymers134,8385
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein/peptide Neuromedin-U-25 / NmU-25


Mass: 3083.398 Da / Num. of mol.: 1 / Source method: obtained synthetically / Details: C-terminal amidation / Source: (synth.) Homo sapiens (human) / References: UniProt: P48645
#2: Protein Neuromedin-U receptor 2 / NMU-R2 / G-protein coupled receptor FM-4 / G-protein coupled receptor TGR-1


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 Guanine nucleotide-binding protein G(i) subunit alpha-1 / Adenylate cyclase-inhibiting G alpha 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 Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


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 Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / G gamma-I


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 interestN
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: NmU25-NMU2-Gi1 complex / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Insecta environmental sample (insect)
Buffer solutionpH: 7.5
Buffer component
IDConc.NameFormulaBuffer-ID
125 mM4- (2-hydroxyethyl)-1-piperazineethanesulfonic acidHEPES1
2150 mMsodium chlorideNaCl1
30.002 mg/mlLauryl Maltose Neopentyl GlycolLMNG1
40.0002 mg/mlCholesteryl hemisuccinateCHS1
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: NICKEL/TITANIUM
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1500 nm / Nominal defocus min: 800 nm
Specimen holderCryogen: NITROGEN
Image recordingElectron dose: 70 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.15.2_3472: / Classification: refinement
EM softwareName: SerialEM / Version: 3.7 / Category: image acquisition
CTF correctionType: NONE
3D reconstructionResolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 912031 / Symmetry type: POINT
RefinementStereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 71.4 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0026943
ELECTRON MICROSCOPYf_angle_d0.4369477
ELECTRON MICROSCOPYf_dihedral_angle_d5.9374050
ELECTRON MICROSCOPYf_chiral_restr0.0381125
ELECTRON MICROSCOPYf_plane_restr0.0031204

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