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- PDB-8k6m: Structural complex of neuropeptide Y receptor 1 -

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Basic information

Entry
Database: PDB / ID: 8k6m
TitleStructural complex of neuropeptide Y receptor 1
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • (Neuropeptide ...) x 2
  • scFV16
KeywordsMEMBRANE PROTEIN / neuropeptide Y receptor 1 / complex
Function / homology
Function and homology information


pancreatic polypeptide receptor activity / peptide YY receptor activity / neuropeptide Y receptor activity / positive regulation of appetite / synaptic signaling via neuropeptide / neuropeptide Y receptor binding / intestinal epithelial cell differentiation / negative regulation of adenylate cyclase-activating adrenergic receptor signaling pathway / neuropeptide receptor activity / adult feeding behavior ...pancreatic polypeptide receptor activity / peptide YY receptor activity / neuropeptide Y receptor activity / positive regulation of appetite / synaptic signaling via neuropeptide / neuropeptide Y receptor binding / intestinal epithelial cell differentiation / negative regulation of adenylate cyclase-activating adrenergic receptor signaling pathway / neuropeptide receptor activity / adult feeding behavior / negative regulation of calcium ion-dependent exocytosis / G protein-coupled adenosine receptor signaling pathway / positive regulation of urine volume / negative regulation of adenylate cyclase activity / neuropeptide hormone activity / positive regulation of neural precursor cell proliferation / negative regulation of synaptic transmission / neuropeptide binding / feeding behavior / gamma-aminobutyric acid signaling pathway / neuronal dense core vesicle / central nervous system neuron development / outflow tract morphogenesis / regulation of calcium ion transport / negative regulation of apoptotic signaling pathway / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / regulation of multicellular organism growth / calcium channel regulator activity / neuropeptide signaling pathway / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / positive regulation of insulin receptor signaling pathway / Adenylate cyclase inhibitory pathway / positive regulation of vascular associated smooth muscle cell proliferation / sensory perception of pain / response to nutrient / hippocampal mossy fiber to CA3 synapse / Peptide ligand-binding receptors / positive regulation of superoxide anion generation / GABA-ergic synapse / locomotory behavior / Regulation of insulin secretion / G protein-coupled receptor binding / G protein-coupled receptor activity / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / cerebral cortex development / regulation of blood pressure / G-protein beta/gamma-subunit complex 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 / adenylate cyclase-activating G protein-coupled receptor signaling pathway / 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 / glucose metabolic process / neuron projection development / 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) / cell body / GTPase binding / Ca2+ pathway / retina development in camera-type eye / midbody / 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 / chemical synaptic transmission / G alpha (q) signalling events
Similarity search - Function
Neuropeptide Y1 receptor / Neuropeptide Y receptor family / Pancreatic hormone-like / Pancreatic hormone-like, conserved site / Pancreatic hormone peptide / Pancreatic hormone family signature. / Pancreatic hormone family profile. / Pancreatic hormones / neuropeptide F / peptide YY family / G-protein alpha subunit, group I / Guanine nucleotide binding protein (G-protein), alpha subunit ...Neuropeptide Y1 receptor / Neuropeptide Y receptor family / Pancreatic hormone-like / Pancreatic hormone-like, conserved site / Pancreatic hormone peptide / Pancreatic hormone family signature. / Pancreatic hormone family profile. / Pancreatic hormones / neuropeptide F / peptide YY family / G-protein alpha subunit, group I / 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. / 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
Pro-neuropeptide Y / Guanine nucleotide-binding protein G(i) subunit alpha-2 / Neuropeptide Y receptor type 1 / 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
Similarity search - Component
Biological speciesHomo sapiens (human)
Mus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsShen, S.Y. / Zhao, C. / Shao, Z.H.
Funding support China, 1items
OrganizationGrant numberCountry
Other government China
CitationJournal: MedComm (2020) / Year: 2024
Title: Structural basis of neuropeptide Y signaling through Y and Y receptors.
Authors: Siyuan Shen / Yue Deng / Chenglong Shen / Haidi Chen / Lin Cheng / Chao Wu / Chang Zhao / Zhiqian Yang / Hanlin Hou / Kexin Wang / Zhenhua Shao / Cheng Deng / Feng Ye / Wei Yan /
Abstract: Neuropeptide Y (NPY), a 36-amino-acid peptide, functions as a neurotransmitter in both the central and peripheral nervous systems by activating the NPY receptor subfamily. Notably, NPY analogs ...Neuropeptide Y (NPY), a 36-amino-acid peptide, functions as a neurotransmitter in both the central and peripheral nervous systems by activating the NPY receptor subfamily. Notably, NPY analogs display varying selectivity and exert diverse physiological effects through their interactions with this receptor family. [Pro]-NPY and [Leu, Pro]-NPY, mainly acting on YR, reportedly increases blood pressure and postsynaptically potentiates the effect of other vasoactive substances above all, while N-terminal cleaved NPY variants in human body primary mediates angiogenesis and neurotransmitter release inhibition through YR. However, the recognition mechanisms of YR and YR with specific agonists remain elusive, thereby hindering subtype receptor-selective drug development. In this study, we report three cryo-electron microscopy (cryo-EM) structures of Gi2-coupled YR and YR in complexes with NPY, as well as YR bound to a selective agonist [Leu, Pro]-NPY. Combined with cell-based assays, our study not only reveals the conserved peptide-binding mode of NPY receptors but also identifies an additional sub-pocket that confers ligand selectivity. Moreover, our analysis of YR evolutionary dynamics suggests that this sub-pocket has undergone functional adaptive evolution across different species. Collectively, our findings shed light on the molecular underpinnings of neuropeptide recognition and receptor activation, and they present a promising avenue for the design of selective drugs targeting the NPY receptor family.
History
DepositionJul 25, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jul 31, 2024Provider: repository / Type: Initial release
Revision 1.1Oct 16, 2024Group: Data collection / Structure summary
Category: em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update
Revision 1.2Feb 12, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.journal_abbrev / _citation.journal_id_CSD ..._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 / _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(i) subunit alpha-2
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
D: Neuropeptide Y receptor type 1
S: scFV16
E: Neuropeptide Y


Theoretical massNumber of molelcules
Total (without water)161,0056
Polymers161,0056
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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

#1: Protein Guanine nucleotide-binding protein G(i) subunit alpha-2 / Adenylate cyclase-inhibiting G alpha protein


Mass: 40516.891 Da / Num. of mol.: 1 / Mutation: S47N,G204A,E246A,A327S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNAI2, GNAI2B / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P04899
#2: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 39141.793 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNB1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P62873
#3: 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: Spodoptera frugiperda (fall armyworm) / References: UniProt: P59768

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Neuropeptide ... , 2 types, 2 molecules DE

#4: Protein Neuropeptide Y receptor type 1 / NPY1-R


Mass: 40569.445 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NPY1R, NPYR, NPYY1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P25929
#6: Protein/peptide Neuropeptide Y / CPON / C-flanking peptide of NPY


Mass: 4278.720 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: P01303

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Antibody , 1 types, 1 molecules S

#5: Antibody scFV16


Mass: 28636.793 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Spodoptera frugiperda (fall armyworm)

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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: Structural complex of neuropeptide Y receptor 1 / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.5
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: 1800 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 57 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 127586 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0039547
ELECTRON MICROSCOPYf_angle_d0.55912926
ELECTRON MICROSCOPYf_dihedral_angle_d4.0621283
ELECTRON MICROSCOPYf_chiral_restr0.0421458
ELECTRON MICROSCOPYf_plane_restr0.0061640

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