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- PDB-7w56: Cryo-EM structure of the neuromedin S-bound neuromedin U receptor... -

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Basic information

Entry
Database: PDB / ID: 7w56
TitleCryo-EM structure of the neuromedin S-bound neuromedin U receptor 1-Gq protein complex
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Neuromedin U Receptor 1
  • Neuromedin-S
  • scFv16
KeywordsSIGNALING PROTEIN / Cryo-EM / GPCR / Neuromedin S / neuromedin U receptor 1 / Gq / complex
Function / homology
Function and homology information


locomotor rhythm / neuropeptide signaling pathway / Peptide ligand-binding receptors / G protein-coupled receptor 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 ...locomotor rhythm / neuropeptide signaling pathway / Peptide ligand-binding receptors / G protein-coupled receptor 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 / 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 / G alpha (z) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / cellular response to catecholamine stimulus / ADP signalling through P2Y purinoceptor 1 / G beta:gamma signalling through PI3Kgamma / adenylate cyclase-activating dopamine receptor signaling pathway / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / 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 / extracellular vesicle / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / GTPase binding / Ca2+ pathway / retina development in camera-type eye / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / fibroblast proliferation / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (i) signalling events / G alpha (s) signalling events / G alpha (q) signalling events / Ras protein signal transduction / 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 / extracellular region / membrane / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Neuromedin S / Neuromedin U, amidation site / Neuromedin U signature. / YVTN repeat-like/Quinoprotein amine dehydrogenase / 7 Propeller / Methylamine Dehydrogenase; Chain H / G-protein, gamma subunit / G-protein gamma subunit domain profile. / G-protein gamma-like domain / G-protein gamma-like domain superfamily ...Neuromedin S / Neuromedin U, amidation site / Neuromedin U signature. / YVTN repeat-like/Quinoprotein amine dehydrogenase / 7 Propeller / Methylamine Dehydrogenase; Chain H / 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 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 / Immunoglobulins / Immunoglobulin-like / Sandwich / Mainly Beta
Similarity search - Domain/homology
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 / Neuromedin-S
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.9 Å
AuthorsYou, C. / Xu, H.E. / Jiang, Y.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)31770796 China
CitationJournal: Nat Commun / Year: 2022
Title: Structural insights into the peptide selectivity and activation of human neuromedin U receptors.
Authors: Chongzhao You / Yumu Zhang / Peiyu Xu / Sijie Huang / Wanchao Yin / H Eric Xu / Yi Jiang /
Abstract: Neuromedin U receptors (NMURs), including NMUR1 and NMUR2, are a group of G-coupled G protein-coupled receptors (GPCRs). NMUR1 and NMUR2 play distinct, pleiotropic physiological functions in ...Neuromedin U receptors (NMURs), including NMUR1 and NMUR2, are a group of G-coupled G protein-coupled receptors (GPCRs). NMUR1 and NMUR2 play distinct, pleiotropic physiological functions in peripheral tissues and in the central nervous system (CNS), respectively, according to their distinct tissue distributions. These receptors are stimulated by two endogenous neuropeptides, neuromedin U and S (NMU and NMS) with similar binding affinities. NMURs have gathered attention as potential drug targets for obesity and inflammatory disorders. Specifically, selective agonists for NMUR2 in peripheral tissue show promising long-term anti-obesity effects with fewer CNS-related side effects. However, the mechanisms of peptide binding specificity and receptor activation remain elusive. Here, we report four cryo-electron microscopy structures of G chimera-coupled NMUR1 and NMUR2 in complexes with NMU and NMS. These structures reveal the conserved overall peptide-binding mode and the mechanism of peptide selectivity for specific NMURs, as well as the common activation mechanism of the NMUR subfamily. Together, these findings provide insights into the molecular basis of the peptide recognition and offer an opportunity for the design of the selective drugs targeting NMURs.
History
DepositionNov 29, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Apr 20, 2022Provider: repository / Type: Initial release
Revision 1.1Jun 15, 2022Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Dec 7, 2022Group: Source and taxonomy / Category: entity_src_gen
Item: _entity_src_gen.pdbx_gene_src_ncbi_taxonomy_id / _entity_src_gen.pdbx_gene_src_scientific_name
Revision 1.3Oct 23, 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Guanine nucleotide-binding protein G(q) subunit alpha
B: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
C: Neuromedin-S
E: scFv16
G: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
R: Neuromedin U Receptor 1


Theoretical massNumber of molelcules
Total (without water)203,7846
Polymers203,7846
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Guanine nucleotide-binding protein ... , 3 types, 3 molecules ABG

#1: Protein Guanine nucleotide-binding protein G(q) subunit alpha


Mass: 41724.383 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Trichoplusia ni (cabbage looper)
#2: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 40226.992 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
#5: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / G gamma-I


Mass: 7729.947 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

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Protein/peptide / Antibody / Protein , 3 types, 3 molecules CER

#3: Protein/peptide Neuromedin-S


Mass: 3927.453 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NMS / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q5H8A3
#4: Antibody scFv16


Mass: 26496.514 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Trichoplusia ni (cabbage looper)
#6: Protein Neuromedin U Receptor 1


Mass: 83678.484 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Trichoplusia ni (cabbage looper)

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Details

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: the neuromedin S-bound neuromedin U receptor 1-Gq protein complex
Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Trichoplusia ni (cabbage looper)
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
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: 2200 nm / Nominal defocus min: 1100 nm
Image recordingElectron dose: 61.8 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.18.2_3874: / Classification: refinement
CTF correctionType: NONE
3D reconstructionResolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 588662 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0049171
ELECTRON MICROSCOPYf_angle_d0.56612423
ELECTRON MICROSCOPYf_dihedral_angle_d16.2043313
ELECTRON MICROSCOPYf_chiral_restr0.0411402
ELECTRON MICROSCOPYf_plane_restr0.0031582

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